Discovery of a Biased Allosteric Modulator for Cannabinoid 1 Receptor: Preclinical Anti-Glaucoma Efficacy

We apply the magic methyl effect to improve the potency/efficacy of GAT211, the prototypic 2-phenylindole-based cannabinoid type-1 receptor (CB1R) agonist-positive allosteric modulator (ago-PAM). Introducing a methyl group at the a-position of nitro group generated two diastereomers, the greater pot...

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Published in:Journal of medicinal chemistry Vol. 64; no. 12; pp. 8104 - 8126
Main Authors: Garai, Sumanta, Leo, Luciana M., Szczesniak, Anna-Maria, Hurst, Dow P., Schaffer, Peter C., Zagzoog, Ayat, Black, Tallan, Deschamps, Jeffrey R., Miess, Elke, Schulz, Stefan, Janero, David R., Straiker, Alex, Pertwee, Roger G., Abood, Mary E., Kelly, Melanie E. M., Reggio, Patricia H., Laprairie, Robert B., Thakur, Ganesh A.
Format: Journal Article
Language:English
Published: WASHINGTON Amer Chemical Soc 24.06.2021
Subjects:
Allosteric Site
Animals
Cannabinoid Receptor Agonists - chemical synthesis
Cannabinoid Receptor Agonists - metabolism
Cannabinoid Receptor Agonists - therapeutic use
Chemistry, Medicinal
CHO Cells
Cricetulus
Glaucoma - drug therapy
HEK293 Cells
Hippocampus - cytology
Humans
Indoles - chemical synthesis
Indoles - metabolism
Indoles - therapeutic use
Intraocular Pressure - drug effects
Life Sciences & Biomedicine
Ligands
Male
Mice
Mice, Inbred C57BL
Molecular Conformation
Molecular Docking Simulation
Molecular Dynamics Simulation
Neurons - drug effects
Pharmacology & Pharmacy
Receptor, Cannabinoid, CB1 - agonists
Receptor, Cannabinoid, CB1 - chemistry
Receptor, Cannabinoid, CB1 - metabolism
Science & Technology
Stereoisomerism
Structure-Activity Relationship
CB1
DRUG DISCOVERY
ENDOCANNABINOID SYSTEM
PROTEIN-COUPLED RECEPTORS
FUNCTIONAL SELECTIVITY
GENERAL FORCE-FIELD
INTRAOCULAR-PRESSURE
BINDING
MU-OPIOID RECEPTOR
AGONIST
ISSN:0022-2623, 1520-4804, 1520-4804
Online Access:Get more information
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Abstract We apply the magic methyl effect to improve the potency/efficacy of GAT211, the prototypic 2-phenylindole-based cannabinoid type-1 receptor (CB1R) agonist-positive allosteric modulator (ago-PAM). Introducing a methyl group at the a-position of nitro group generated two diastereomers, the greater potency and efficacy of erythro, (+/-)-9 vs threo, (+/-)-10 constitutes the first demonstration of diastereoselective CB1R-allosteric modulator interaction. Of the (+/-)-9 enantiomers, (-)-(S,R)-13 evidenced improved potency over GAT211 as a CB1R ago-PAM, whereas (+)-(R,S)-14 was a CB1R allosteric agonist biased toward G protein- vs beta-arrestin1/2-dependent signaling. (-)-(S,R)-13 and (+)-(R,S)-14 were devoid of undesirable side effects (triad test), and (+)-(R,S)-14 reduced intraocular pressure with an unprecedentedly long duration of action in a murine glaucoma model. (-)-(S,R)-13 docked into both a CB1R extracellular PAM and intracellular allosteric-agonist site(s), whereas (+)-(R,S)-I4 preferentially engaged only the latter. Exploiting G-protein biased CB1R-allosteric modulation can offer safer therapeutic candidates for glaucoma and, potentially, other diseases.
AbstractList We apply the magic methyl effect to improve the potency/efficacy of GAT211, the prototypic 2-phenylindole-based cannabinoid type-1 receptor (CB1R) agonist-positive allosteric modulator (ago-PAM). Introducing a methyl group at the α-position of nitro group generated two diastereomers, the greater potency and efficacy of , (±)- vs , (±)- constitutes the first demonstration of diastereoselective CB1R-allosteric modulator interaction. Of the (±)- enantiomers, (-)-( , )- evidenced improved potency over GAT211 as a CB1R ago-PAM, whereas (+)-( , )- was a CB1R allosteric agonist biased toward G protein- vs β-arrestin1/2-dependent signaling. (-)-( , )- and (+)-( , )- were devoid of undesirable side effects (triad test), and (+)-( , )- reduced intraocular pressure with an unprecedentedly long duration of action in a murine glaucoma model. (-)-( , )- docked into both a CB1R extracellular PAM and intracellular allosteric-agonist site(s), whereas (+)-( , )- preferentially engaged only the latter. Exploiting G-protein biased CB1R-allosteric modulation can offer safer therapeutic candidates for glaucoma and, potentially, other diseases.
We apply the magic methyl effect to improve the potency/efficacy of GAT211, the prototypic 2-phenylindole-based cannabinoid type-1 receptor (CB1R) agonist-positive allosteric modulator (ago-PAM). Introducing a methyl group at the a-position of nitro group generated two diastereomers, the greater potency and efficacy of erythro, (+/-)-9 vs threo, (+/-)-10 constitutes the first demonstration of diastereoselective CB1R-allosteric modulator interaction. Of the (+/-)-9 enantiomers, (-)-(S,R)-13 evidenced improved potency over GAT211 as a CB1R ago-PAM, whereas (+)-(R,S)-14 was a CB1R allosteric agonist biased toward G protein- vs beta-arrestin1/2-dependent signaling. (-)-(S,R)-13 and (+)-(R,S)-14 were devoid of undesirable side effects (triad test), and (+)-(R,S)-14 reduced intraocular pressure with an unprecedentedly long duration of action in a murine glaucoma model. (-)-(S,R)-13 docked into both a CB1R extracellular PAM and intracellular allosteric-agonist site(s), whereas (+)-(R,S)-I4 preferentially engaged only the latter. Exploiting G-protein biased CB1R-allosteric modulation can offer safer therapeutic candidates for glaucoma and, potentially, other diseases.
We apply the magic methyl effect to improve the potency/efficacy of GAT211, the prototypic 2-phenylindole-based cannabinoid type-1 receptor (CB1R) agonist-positive allosteric modulator (ago-PAM). Introducing a methyl group at the α-position of nitro group generated two diastereomers, the greater potency and efficacy of erythro, (±)-9 vs threo, (±)-10 constitutes the first demonstration of diastereoselective CB1R-allosteric modulator interaction. Of the (±)-9 enantiomers, (-)-(S,R)-13 evidenced improved potency over GAT211 as a CB1R ago-PAM, whereas (+)-(R,S)-14 was a CB1R allosteric agonist biased toward G protein- vs β-arrestin1/2-dependent signaling. (-)-(S,R)-13 and (+)-(R,S)-14 were devoid of undesirable side effects (triad test), and (+)-(R,S)-14 reduced intraocular pressure with an unprecedentedly long duration of action in a murine glaucoma model. (-)-(S,R)-13 docked into both a CB1R extracellular PAM and intracellular allosteric-agonist site(s), whereas (+)-(R,S)-14 preferentially engaged only the latter. Exploiting G-protein biased CB1R-allosteric modulation can offer safer therapeutic candidates for glaucoma and, potentially, other diseases.We apply the magic methyl effect to improve the potency/efficacy of GAT211, the prototypic 2-phenylindole-based cannabinoid type-1 receptor (CB1R) agonist-positive allosteric modulator (ago-PAM). Introducing a methyl group at the α-position of nitro group generated two diastereomers, the greater potency and efficacy of erythro, (±)-9 vs threo, (±)-10 constitutes the first demonstration of diastereoselective CB1R-allosteric modulator interaction. Of the (±)-9 enantiomers, (-)-(S,R)-13 evidenced improved potency over GAT211 as a CB1R ago-PAM, whereas (+)-(R,S)-14 was a CB1R allosteric agonist biased toward G protein- vs β-arrestin1/2-dependent signaling. (-)-(S,R)-13 and (+)-(R,S)-14 were devoid of undesirable side effects (triad test), and (+)-(R,S)-14 reduced intraocular pressure with an unprecedentedly long duration of action in a murine glaucoma model. (-)-(S,R)-13 docked into both a CB1R extracellular PAM and intracellular allosteric-agonist site(s), whereas (+)-(R,S)-14 preferentially engaged only the latter. Exploiting G-protein biased CB1R-allosteric modulation can offer safer therapeutic candidates for glaucoma and, potentially, other diseases.
Author Schulz, Stefan
Zagzoog, Ayat
Deschamps, Jeffrey R.
Straiker, Alex
Miess, Elke
Reggio, Patricia H.
Leo, Luciana M.
Schaffer, Peter C.
Thakur, Ganesh A.
Abood, Mary E.
Szczesniak, Anna-Maria
Black, Tallan
Pertwee, Roger G.
Hurst, Dow P.
Laprairie, Robert B.
Garai, Sumanta
Janero, David R.
Kelly, Melanie E. M.
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  organization: Northeastern Univ, Bouve Coll Hlth Sci, Dept Pharmaceut Sci, Boston, MA 02115 USA
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  orcidid: 0000-0002-9676-937X
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  organization: Temple Univ, Ctr Subst Abuse Res, Lewis Katz Sch Med, Philadelphia, PA 19140 USA
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  givenname: Anna-Maria
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  organization: Dalhousie Univ, Dept Pharmacol, Halifax, NS B3H 4R2, Canada
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  givenname: Dow P.
  surname: Hurst
  fullname: Hurst, Dow P.
  organization: Univ North Carolina Greensboro, Ctr Drug Discovery, Greensboro, NC 27402 USA
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  fullname: Zagzoog, Ayat
  organization: Univ Saskatchewan, Coll Pharm & Nutr, Saskatoon, SK S7N 2Z4, Canada
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  surname: Black
  fullname: Black, Tallan
  organization: Univ Saskatchewan, Coll Pharm & Nutr, Saskatoon, SK S7N 2Z4, Canada
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  givenname: Jeffrey R.
  surname: Deschamps
  fullname: Deschamps, Jeffrey R.
  organization: Naval Res Lab, Washington, DC 20375 USA
– sequence: 9
  givenname: Elke
  surname: Miess
  fullname: Miess, Elke
  organization: Friedrich Schiller Univ Jena, Dept Pharmacol & Toxicol, Jena Univ Hosp, D-07747 Jena, Germany
– sequence: 10
  givenname: Stefan
  surname: Schulz
  fullname: Schulz, Stefan
  organization: Friedrich Schiller Univ Jena, Dept Pharmacol & Toxicol, Jena Univ Hosp, D-07747 Jena, Germany
– sequence: 11
  givenname: David R.
  orcidid: 0000-0002-4633-1038
  surname: Janero
  fullname: Janero, David R.
  organization: Northeastern Univ, Bouve Coll Hlth Sci, Dept Pharmaceut Sci, Boston, MA 02115 USA
– sequence: 12
  givenname: Alex
  surname: Straiker
  fullname: Straiker, Alex
  organization: Indiana Univ, Gill Ctr, Bloomington, IN 47405 USA
– sequence: 13
  givenname: Roger G.
  surname: Pertwee
  fullname: Pertwee, Roger G.
  organization: Univ Aberdeen, Sch Med Med Sci & Nutr, Inst Med Sci, Aberdeen AB25 2ZD, Scotland
– sequence: 14
  givenname: Mary E.
  orcidid: 0000-0002-1744-2820
  surname: Abood
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  givenname: Melanie E. M.
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  givenname: Robert B.
  surname: Laprairie
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  email: robert.laprairie@usask.ca
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  givenname: Ganesh A.
  orcidid: 0000-0002-7468-8819
  surname: Thakur
  fullname: Thakur, Ganesh A.
  email: g.thakur@northeastern.edu
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Cites_doi 10.1111/papr.12801
10.1677/JME-08-0190
10.3389/fnmol.2019.00257
10.1371/journal.pone.0000880
10.1113/jphysiol.2005.091918
10.1016/j.biopsych.2017.06.032
10.1089/jop.2017.0037
10.1016/j.bmc.2020.115727
10.1016/j.neuron.2015.03.063
10.3389/fendo.2014.00068
10.1016/bs.mie.2017.06.031
10.1089/can.2016.0028
10.1021/ci3003649
10.1124/mol.105.016162
10.1517/14728214.2012.660916
10.1016/j.bcp.2016.11.014
10.1016/j.coph.2020.08.014
10.1093/nar/gkr703
10.1016/j.drudis.2016.08.005
10.1016/j.lfs.2003.07.005
10.1155/2016/9364091
10.4062/biomolther.2016.165
10.1038/NMETH.4067
10.1167/iovs.10-5993
10.1016/j.pbb.2020.173059
10.1124/jpet.117.240192
10.3390/ijms21207693
10.1002/med.21418
10.1038/nrd1495
10.3390/molecules25020417
10.1124/pr.58.3.2
10.1089/can.2016.0037
10.1080/03602532.2018.1428342
10.1111/adb.12843
10.1002/jhet.2861
10.1021/acs.jmedchem.9b01142
10.1002/med.21318
10.1002/jcc.21367
10.1002/anie.201303207
10.1523/JNEUROSCI.1937-15.2015
10.1021/ct400314y
10.1038/nrd2553
10.1038/s41401-018-0164-x
10.1002/jcc.23422
10.1124/jpet.112.201616
10.1021/jm4010829
10.1002/jcc.20290
10.1080/17460441.2016.1245289
10.1021/acs.jctc.5b00935
10.1155/2020/6138132
10.1021/acsmedchemlett.9b00256
10.1021/acs.jmedchem.8b00435
10.1126/scisignal.aas9609
10.1124/mol.114.096503
10.3389/fnmol.2020.00054
10.1002/qua.24481
10.1021/cn200111m
10.1016/bs.mie.2017.06.018
10.1139/cjpp-2016-0346
10.3390/ijms20235874
10.1021/acs.jmedchem.9b00640
10.1021/jp101759q
10.1021/acs.jmedchem.8b00642
10.1021/cr200060g
10.1124/jpet.111.185769
10.1124/mol.115.101980
10.1016/j.tips.2007.10.006
10.1161/CIRCRESAHA.110.231308
10.1016/j.neuropharm.2019.03.033
10.1111/bph.12937
10.1038/npp.2015.148
10.1007/s00213-020-05650-5
10.1021/jm3003697
10.1016/j.phrs.2017.11.019
10.1021/acschemneuro.6b00310
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Issue 12
Keywords CB1
DRUG DISCOVERY
ENDOCANNABINOID SYSTEM
PROTEIN-COUPLED RECEPTORS
FUNCTIONAL SELECTIVITY
GENERAL FORCE-FIELD
INTRAOCULAR-PRESSURE
BINDING
MU-OPIOID RECEPTOR
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References Vanommeslaeghe, K (WOS:000274922000002) 2010; 31
Jarvinen, T (WOS:000177961500011) 2002; 95
Sholler, DJ (WOS:000599514000011) 2020; 199
STOCKTON, JM (WOS:A1983QP72800002) 1983; 23
Cairns, EA (WOS:000371059300001) 2016; 2016
EHLERT, FJ (WOS:A1988M150000010) 1988; 33
Mitjavila, J (WOS:000428102600044) 2018; 129
Huang, J (WOS:000391162300029) 2017; 14
Cvenkel, B (WOS:000559033700004) 2020; 2020
Nguyen, T (WOS:000399460800001) 2017; 37
Mayne, CG (WOS:000326466900001) 2013; 34
Kim, Y (WOS:000442960800017) 2018; 61
Slivicki, RA (WOS:000447896300007) 2018; 84
Thapa, D (WOS:000515381800179) 2020; 25
Pacher, P (WOS:000240465500004) 2006; 58
Lu, Y (WOS:000398837600001) 2017; 95
Mennucci, B. (000668340800012.77) 1000
Ballesteros, J. A. (000668340800012.74) 1995; 25
Leung, CS (WOS:000303785900034) 2012; 55
Stahl, EL (WOS:000352998500001) 2015; 87
Turu, G (WOS:000275774300001) 2010; 44
Kulkarni, PM (WOS:000401732500047) 2017; 54
Laprairie, RB (WOS:000404098100010) 2017; 8
Lomize, MA (WOS:000298601300054) 2012; 40
Neuhofer, D (WOS:000496650700001) 2020; 25
Laprairie, RB (WOS:000370511100004) 2016; 89
Laprairie, RB (WOS:000414264200013) 2017; 593
Garai, S (WOS:000509438800006) 2020; 63
Janero, DR (WOS:000387481200009) 2016; 11
Vanommeslaeghe, K (WOS:000312563800006) 2012; 52
Schaffer, PC (WOS:000582711600008) 2020; 28
Kenakin, T (WOS:000301898000007) 2012; 3
Ross, RA (WOS:000251402900004) 2007; 28
Grim, TW (WOS:000405930600007) 2017; 362
BEKKERS, JM (WOS:A1991GC99200080) 1991; 88
Janero, DR (WOS:000302025800004) 2012; 17
Schneider, M (WOS:000366051800018) 2015; 35
Salomon-Ferrer, R (WOS:000330096800004) 2013; 9
Mao, M (WOS:000290111000023) 2011; 52
Khoury, E (WOS:000209749800070) 2014; 5
Tao, Q (WOS:000073585000035) 1998; 285
Laprairie, RB (WOS:000494330500001) 2019; 12
Laprairie, RB (WOS:000468707900001) 2019; 151
DeWire, SM (WOS:000315192500017) 2013; 344
BLACK, JW (WOS:A1983RX01600001) 1983; 220
Lee, J (WOS:000368322500038) 2016; 12
Price, MR (WOS:000232832900029) 2005; 68
Cairns, EA (WOS:000412014100003) 2017; 33
Slivicki, RA (WOS:000534248500001) 2020; 13
Hudson, BD (WOS:000297267800003) 2011; 339
Laine, K (WOS:000178298400012) 2002; 43
Klauda, JB (WOS:000278479900016) 2010; 114
Hryhorowicz, S (WOS:000504428300056) 2019; 20
Di Marzo, V (WOS:000223654800020) 2004; 3
Saha, D (WOS:000509438800001) 2020; 63
Al-Zoubi, R. (000668340800012.26) 2019; 20
Vallee, M. (000668340800012.27) 1000
Singla, NK (WOS:000485304600003) 2019; 19
Jo, S (WOS:000207455600026) 2007; 2
Gamage, TF (WOS:000587907800004) 2016; 1
Aizpurua-Olaizola, O (WOS:000392787800011) 2017; 22
Harrison, C (WOS:000186642400008) 2003; 74
Barreiro, EJ (WOS:000295542700002) 2011; 111
Haspula, D (WOS:000585517700001) 2020; 21
Bologna, Z (WOS:000392457500003) 2017; 25
Miess, E (WOS:000438973900003) 2018; 11
Rook, JM (WOS:000354878400016) 2015; 86
Cook, AE (WOS:000346657300014) 2015; 172
LEVISON, SW (WOS:A1991GA37900008) 1991; 57
Schonherr, H (WOS:000326807900011) 2013; 52
Chen, XT (WOS:000326259900027) 2013; 56
Case, DA (WOS:000233021400002) 2005; 26
Hurst, DP (WOS:000480500000020) 2019; 10
Mallipeddi, S (WOS:000395354800001) 2017; 128
DeWire, SM (WOS:000292511700011) 2011; 109
Ibsen, MS (WOS:000587911300003) 2017; 2
Bochevarov, AD (WOS:000322716700002) 2013; 113
Tan, L (WOS:000451496300003) 2018; 61
Brooks, WH (WOS:000289768900001) 2011; 11
Chien, FY (WOS:000180306800012) 2003; 121
Ignatowska-Jankowska, BM (WOS:000364858200011) 2015; 40
Lujan, MA (WOS:000640339100005) 2021; 56
Dopart, R (WOS:000426911700002) 2018; 50
PERTWEE, RG (WOS:A1972O429800016) 1972; 46
Straiker, A (WOS:000233622300013) 2005; 569
Shonberg, J (WOS:000343826600006) 2014; 34
FURSHPAN, EJ (WOS:A1976CN11500093) 1976; 73
Lu, D (WOS:000458791700004) 2019; 40
Di Marzo, V (WOS:000255419900017) 2008; 7
Datta, U (WOS:000563635600002) 2020
Kulkarni, AR (WOS:000414264200014) 2017; 593
34019766 - J Med Chem. 2021 Jun 24;64(12):8101-8103
References_xml – volume: 57
  start-page: 782
  year: 1991
  ident: WOS:A1991GA37900008
  article-title: CHARACTERIZATION AND PARTIAL-PURIFICATION OF AIM - A PLASMA-PROTEIN THAT INDUCES RAT CEREBRAL TYPE-2 ASTROGLIA FROM BIPOTENTIAL GLIAL PROGENITORS
  publication-title: JOURNAL OF NEUROCHEMISTRY
– volume: 19
  start-page: 715
  year: 2019
  ident: WOS:000485304600003
  article-title: APOLLO-2: A Randomized, Placebo and Active-Controlled Phase III Study Investigating Oliceridine (TRV130), a G Protein-Biased Ligand at the mu-Opioid Receptor, for Management of Moderate to Severe Acute Pain Following Abdominoplasty
  publication-title: PAIN PRACTICE
  doi: 10.1111/papr.12801
– volume: 44
  start-page: 75
  year: 2010
  ident: WOS:000275774300001
  article-title: Signal transduction of the CB1 cannabinoid receptor
  publication-title: JOURNAL OF MOLECULAR ENDOCRINOLOGY
  doi: 10.1677/JME-08-0190
– volume: 12
  start-page: ARTN 257
  year: 2019
  ident: WOS:000494330500001
  article-title: Indomethacin Enhances Type 1 Cannabinoid Receptor Signaling
  publication-title: FRONTIERS IN MOLECULAR NEUROSCIENCE
  doi: 10.3389/fnmol.2019.00257
– volume: 121
  start-page: 87
  year: 2003
  ident: WOS:000180306800012
  article-title: Effect of WIN 55212-2, a cannabinoid receptor agonist, on aqueous humor dynamics in monkeys
  publication-title: ARCHIVES OF OPHTHALMOLOGY
– volume: 2
  start-page: ARTN e880
  year: 2007
  ident: WOS:000207455600026
  article-title: Automated Builder and Database of Protein/Membrane Complexes for Molecular Dynamics Simulations
  publication-title: PLOS ONE
  doi: 10.1371/journal.pone.0000880
– volume: 569
  start-page: 501
  year: 2005
  ident: WOS:000233622300013
  article-title: Depolarization-induced suppression of excitation in murine autaptic hippocampal neurones
  publication-title: JOURNAL OF PHYSIOLOGY-LONDON
  doi: 10.1113/jphysiol.2005.091918
– volume: 95
  start-page: 203
  year: 2002
  ident: WOS:000177961500011
  article-title: Cannabinoids in the treatment of glaucoma
  publication-title: PHARMACOLOGY & THERAPEUTICS
– volume: 73
  start-page: 4225
  year: 1976
  ident: WOS:A1976CN11500093
  article-title: CHEMICAL TRANSMISSION BETWEEN RAT SYMPATHETIC NEURONS AND CARDIAC MYOCYTES DEVELOPING IN MICROCULTURES - EVIDENCE FOR CHOLINERGIC, ADRENERGIC, AND DUAL-FUNCTION NEURONS
  publication-title: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
– volume: 84
  start-page: 722
  year: 2018
  ident: WOS:000447896300007
  article-title: Positive Allosteric Modulation of Cannabinoid Receptor Type 1 Suppresses Pathological Pain Without Producing Tolerance or Dependence
  publication-title: BIOLOGICAL PSYCHIATRY
  doi: 10.1016/j.biopsych.2017.06.032
– volume: 33
  start-page: 582
  year: 2017
  ident: WOS:000412014100003
  article-title: The In Vivo Effects of the CB1-Positive Allosteric Modulator GAT229 on Intraocular Pressure in Ocular Normotensive and Hypertensive Mice
  publication-title: JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS
  doi: 10.1089/jop.2017.0037
– volume: 28
  start-page: ARTN 115727
  year: 2020
  ident: WOS:000582711600008
  article-title: Focused structure-activity relationship profiling around the 2-phenylindole scaffold of a cannabinoid type-1 receptor agonist-positive allosteric modulator: site-III aromatic-ring congeners with enhanced activity and solubility
  publication-title: BIOORGANIC & MEDICINAL CHEMISTRY
  doi: 10.1016/j.bmc.2020.115727
– year: 1000
  ident: 000668340800012.27
  publication-title: Pregnenolone can protect the brain from cannabis intoxication
– volume: 86
  start-page: 1029
  year: 2015
  ident: WOS:000354878400016
  article-title: Biased mGlu(5)-Positive Allosteric Modulators Provide In Vivo Efficacy without Potentiating mGlu(5) Modulation of NMDAR Currents
  publication-title: NEURON
  doi: 10.1016/j.neuron.2015.03.063
– volume: 5
  start-page: ARTN 68
  year: 2014
  ident: WOS:000209749800070
  article-title: Allosteric and biased G protein-coupled receptor signaling regulation: potentials for new therapeutics
  publication-title: FRONTIERS IN ENDOCRINOLOGY
  doi: 10.3389/fendo.2014.00068
– volume: 25
  start-page: 366
  year: 1995
  ident: 000668340800012.74
  article-title: Integrated Methods for the Construction of Three-dimensional Models and Computational Probing of Structure-function Relations in G Proteincoupled Receptors
  publication-title: Methods in Neuroscience
– volume: 593
  start-page: 259
  year: 2017
  ident: WOS:000414264200013
  article-title: Approaches to Assess Biased Signaling at the CB1R Receptor
  publication-title: CANNABINOIDS AND THEIR RECEPTORS
  doi: 10.1016/bs.mie.2017.06.031
– volume: 1
  start-page: 272
  year: 2016
  ident: WOS:000587907800004
  article-title: CB1 Allosteric Modulator Org27569 Is an Antagonist/Inverse Agonist of ERK1/2 Signaling
  publication-title: CANNABIS AND CANNABINOID RESEARCH
  doi: 10.1089/can.2016.0028
– volume: 52
  start-page: 3155
  year: 2012
  ident: WOS:000312563800006
  article-title: Automation of the CHARMM General Force Field (CGenFF) II: Assignment of Bonded Parameters and Partial Atomic Charges
  publication-title: JOURNAL OF CHEMICAL INFORMATION AND MODELING
  doi: 10.1021/ci3003649
– volume: 68
  start-page: 1484
  year: 2005
  ident: WOS:000232832900029
  article-title: Allosteric modulation of the cannabinoid CB1 receptor
  publication-title: MOLECULAR PHARMACOLOGY
  doi: 10.1124/mol.105.016162
– volume: 17
  start-page: 17
  year: 2012
  ident: WOS:000302025800004
  article-title: Cannabinoid-1 receptor (CB1R) blockers as medicines: beyond obesity and cardiometabolic disorders to substance abuse/drug addiction with CB1R neutral antagonists
  publication-title: EXPERT OPINION ON EMERGING DRUGS
  doi: 10.1517/14728214.2012.660916
– volume: 128
  start-page: 1
  year: 2017
  ident: WOS:000395354800001
  article-title: Functional selectivity at G-protein coupled receptors: Advancing cannabinoid receptors as drug targets
  publication-title: BIOCHEMICAL PHARMACOLOGY
  doi: 10.1016/j.bcp.2016.11.014
– volume: 56
  start-page: 29
  year: 2021
  ident: WOS:000640339100005
  article-title: Choosing the right drug: status and future of endocannabinoid research for the prevention of drug-seeking reinstatement
  publication-title: CURRENT OPINION IN PHARMACOLOGY
  doi: 10.1016/j.coph.2020.08.014
– volume: 40
  start-page: D370
  year: 2012
  ident: WOS:000298601300054
  article-title: OPM database and PPM web server: resources for positioning of proteins in membranes
  publication-title: NUCLEIC ACIDS RESEARCH
  doi: 10.1093/nar/gkr703
– volume: 22
  start-page: 105
  year: 2017
  ident: WOS:000392787800011
  article-title: Targeting the endocannabinoid system: future therapeutic strategies
  publication-title: DRUG DISCOVERY TODAY
  doi: 10.1016/j.drudis.2016.08.005
– volume: 74
  start-page: 489
  year: 2003
  ident: WOS:000186642400008
  article-title: The [S-35]GTP gamma S binding assay: approaches and applications in pharmacology
  publication-title: LIFE SCIENCES
  doi: 10.1016/j.lfs.2003.07.005
– volume: 2016
  start-page: ARTN 9364091
  year: 2016
  ident: WOS:000371059300001
  article-title: The Endocannabinoid System as a Therapeutic Target in Glaucoma
  publication-title: NEURAL PLASTICITY
  doi: 10.1155/2016/9364091
– volume: 25
  start-page: 12
  year: 2017
  ident: WOS:000392457500003
  article-title: Biased G Protein-Coupled Receptor Signaling: New Player in Modulating Physiology and Pathology
  publication-title: BIOMOLECULES & THERAPEUTICS
  doi: 10.4062/biomolther.2016.165
– volume: 14
  start-page: 71
  year: 2017
  ident: WOS:000391162300029
  article-title: CHARMM36m: an improved force field for folded and intrinsically disordered proteins
  publication-title: NATURE METHODS
  doi: 10.1038/NMETH.4067
– volume: 52
  start-page: 2679
  year: 2011
  ident: WOS:000290111000023
  article-title: Anterior Segment Dysgenesis and Early-Onset Glaucoma in nee Mice with Mutation of Sh3pxd2b
  publication-title: INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
  doi: 10.1167/iovs.10-5993
– volume: 199
  start-page: ARTN 173059
  year: 2020
  ident: WOS:000599514000011
  article-title: Therapeutic potential and safety considerations for the clinical use of synthetic cannabinoids
  publication-title: PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
  doi: 10.1016/j.pbb.2020.173059
– volume: 362
  start-page: 210
  year: 2017
  ident: WOS:000405930600007
  article-title: Apparent CB1 Receptor Rimonabant Affinity Estimates: Combination with THC and Synthetic Cannabinoids in the Mouse In Vivo Triad Model
  publication-title: JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
  doi: 10.1124/jpet.117.240192
– volume: 21
  start-page: ARTN 7693
  year: 2020
  ident: WOS:000585517700001
  article-title: Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases
  publication-title: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
  doi: 10.3390/ijms21207693
– volume: 37
  start-page: 441
  year: 2017
  ident: WOS:000399460800001
  article-title: Allosteric Modulation: An Alternate Approach Targeting the Cannabinoid CB1 Receptor
  publication-title: MEDICINAL RESEARCH REVIEWS
  doi: 10.1002/med.21418
– volume: 3
  start-page: 771
  year: 2004
  ident: WOS:000223654800020
  article-title: The endocannabinoid system and its therapeutic exploitation
  publication-title: NATURE REVIEWS DRUG DISCOVERY
  doi: 10.1038/nrd1495
– volume: 25
  start-page: ARTN 417
  year: 2020
  ident: WOS:000515381800179
  article-title: Allosteric Cannabinoid Receptor 1 (CB1) Ligands Reduce Ocular Pain and Inflammation
  publication-title: MOLECULES
  doi: 10.3390/molecules25020417
– volume: 58
  start-page: 389
  year: 2006
  ident: WOS:000240465500004
  article-title: The endocannabinoid system as an emerging target of pharmacotherapy
  publication-title: PHARMACOLOGICAL REVIEWS
  doi: 10.1124/pr.58.3.2
– volume: 2
  start-page: 48
  year: 2017
  ident: WOS:000587911300003
  article-title: Cannabinoid CB1 and CB2 Receptor Signaling and Bias
  publication-title: CANNABIS AND CANNABINOID RESEARCH
  doi: 10.1089/can.2016.0037
– volume: 50
  start-page: 3
  year: 2018
  ident: WOS:000426911700002
  article-title: Allosteric modulators of cannabinoid receptor 1: developing compounds for improved specificity
  publication-title: DRUG METABOLISM REVIEWS
  doi: 10.1080/03602532.2018.1428342
– volume: 25
  start-page: ARTN e12843
  year: 2020
  ident: WOS:000496650700001
  article-title: The loss of NMDAR-dependent LTD following cannabinoid self-administration is restored by positive allosteric modulation of CB1 receptors
  publication-title: ADDICTION BIOLOGY
  doi: 10.1111/adb.12843
– volume: 54
  start-page: 2079
  year: 2017
  ident: WOS:000401732500047
  article-title: Microwave-accelerated Conjugate Addition of 2-Arylindoles to Substituted -Nitrostyrenes in the Presence of Ammonium Trifluoroacetate: An Efficient Approach for the Synthesis of a Novel Class of CB1 Cannabinoid Receptor Allosteric Modulators
  publication-title: JOURNAL OF HETEROCYCLIC CHEMISTRY
  doi: 10.1002/jhet.2861
– volume: 63
  start-page: 542
  year: 2020
  ident: WOS:000509438800006
  article-title: Application of Fluorine- and Nitrogen-Walk Approaches: Defining the Structural and Functional Diversity of 2-Phenylindole Class of Cannabinoid 1 Receptor Positive Allosteric Modulators
  publication-title: JOURNAL OF MEDICINAL CHEMISTRY
  doi: 10.1021/acs.jmedchem.9b01142
– volume: 34
  start-page: 1286
  year: 2014
  ident: WOS:000343826600006
  article-title: Biased Agonism at G Protein-Coupled Receptors: The Promise and the Challenges-A Medicinal Chemistry Perspective
  publication-title: MEDICINAL RESEARCH REVIEWS
  doi: 10.1002/med.21318
– volume: 31
  start-page: 671
  year: 2010
  ident: WOS:000274922000002
  article-title: CHARMM General Force Field: A Force Field for Drug-Like Molecules Compatible with the CHARMM All-Atom Additive Biological Force Fields
  publication-title: JOURNAL OF COMPUTATIONAL CHEMISTRY
  doi: 10.1002/jcc.21367
– volume: 220
  start-page: 141
  year: 1983
  ident: WOS:A1983RX01600001
  article-title: OPERATIONAL MODELS OF PHARMACOLOGICAL AGONISM
  publication-title: PROCEEDINGS OF THE ROYAL SOCIETY SERIES B-BIOLOGICAL SCIENCES
– volume: 52
  start-page: 12256
  year: 2013
  ident: WOS:000326807900011
  article-title: Profound Methyl Effects in Drug Discovery and a Call for New C-H Methylation Reactions
  publication-title: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
  doi: 10.1002/anie.201303207
– volume: 35
  start-page: 13975
  year: 2015
  ident: WOS:000366051800018
  article-title: Enhanced Functional Activity of the Cannabinoid Type-1 Receptor Mediates Adolescent Behavior
  publication-title: JOURNAL OF NEUROSCIENCE
  doi: 10.1523/JNEUROSCI.1937-15.2015
– volume: 9
  start-page: 3878
  year: 2013
  ident: WOS:000330096800004
  article-title: Routine Microsecond Molecular Dynamics Simulations with AMBER on GPUs. 2. Explicit Solvent Particle Mesh Ewald
  publication-title: JOURNAL OF CHEMICAL THEORY AND COMPUTATION
  doi: 10.1021/ct400314y
– volume: 46
  start-page: 753
  year: 1972
  ident: WOS:A1972O429800016
  article-title: RING TEST - QUANTITATIVE METHOD FOR ASSESSING CATALEPTIC EFFECT OF CANNABIS IN MICE
  publication-title: BRITISH JOURNAL OF PHARMACOLOGY
– volume: 7
  start-page: 438
  year: 2008
  ident: WOS:000255419900017
  article-title: Targeting the endocannabinoid system: to enhance or reduce?
  publication-title: NATURE REVIEWS DRUG DISCOVERY
  doi: 10.1038/nrd2553
– volume: 40
  start-page: 324
  year: 2019
  ident: WOS:000458791700004
  article-title: Translational potential of allosteric modulators targeting the cannabinoid CB1 receptor
  publication-title: ACTA PHARMACOLOGICA SINICA
  doi: 10.1038/s41401-018-0164-x
– volume: 34
  start-page: 2757
  year: 2013
  ident: WOS:000326466900001
  article-title: Rapid Parameterization of Small Molecules Using the Force Field Toolkit
  publication-title: JOURNAL OF COMPUTATIONAL CHEMISTRY
  doi: 10.1002/jcc.23422
– volume: 344
  start-page: 708
  year: 2013
  ident: WOS:000315192500017
  article-title: A G Protein-Biased Ligand at the mu-Opioid Receptor Is Potently Analgesic with Reduced Gastrointestinal and Respiratory Dysfunction Compared with Morphines
  publication-title: JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
  doi: 10.1124/jpet.112.201616
– volume: 56
  start-page: 8019
  year: 2013
  ident: WOS:000326259900027
  article-title: Structure Activity Relationships and Discovery of a G Protein Biased mu Opioid Receptor Ligand, [(3-Methoxythiophen-2-yl)methyl]a2[(9R)-9-(pyridin-2-y1)-6-oxaspiro-[4.5]clecan-9-yl]ethylpamine (TRV130), for the Treatment of Acute Severe Pain
  publication-title: JOURNAL OF MEDICINAL CHEMISTRY
  doi: 10.1021/jm4010829
– volume: 88
  start-page: 7834
  year: 1991
  ident: WOS:A1991GC99200080
  article-title: EXCITATORY AND INHIBITORY AUTAPTIC CURRENTS IN ISOLATED HIPPOCAMPAL-NEURONS MAINTAINED IN CELL-CULTURE
  publication-title: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
– volume: 26
  start-page: 1668
  year: 2005
  ident: WOS:000233021400002
  article-title: The Amber biomolecular simulation programs
  publication-title: JOURNAL OF COMPUTATIONAL CHEMISTRY
  doi: 10.1002/jcc.20290
– volume: 11
  start-page: 1223
  year: 2016
  ident: WOS:000387481200009
  article-title: Leveraging allostery to improve G protein-coupled receptor (GPCR)-directed therapeutics: cannabinoid receptor 1 as discovery target
  publication-title: EXPERT OPINION ON DRUG DISCOVERY
  doi: 10.1080/17460441.2016.1245289
– volume: 11
  start-page: 760
  year: 2011
  ident: WOS:000289768900001
  article-title: The Significance of Chirality in Drug Design and Development
  publication-title: CURRENT TOPICS IN MEDICINAL CHEMISTRY
– volume: 12
  start-page: 405
  year: 2016
  ident: WOS:000368322500038
  article-title: CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field
  publication-title: JOURNAL OF CHEMICAL THEORY AND COMPUTATION
  doi: 10.1021/acs.jctc.5b00935
– volume: 2020
  start-page: ARTN 6138132
  year: 2020
  ident: WOS:000559033700004
  article-title: Current Medical Therapy and Future Trends in the Management of Glaucoma Treatment
  publication-title: JOURNAL OF OPHTHALMOLOGY
  doi: 10.1155/2020/6138132
– volume: 20
  year: 2019
  ident: 000668340800012.26
  article-title: Structural insights into CB1 receptor biased signaling
  publication-title: Int. J. Mol. Sci.
– volume: 10
  start-page: 1216
  year: 2019
  ident: WOS:000480500000020
  article-title: Identification of CB1 Receptor Allosteric Sites Using Force-Biased MMC Simulated Annealing and Validation by Structure-Activity Relationship Studies
  publication-title: ACS MEDICINAL CHEMISTRY LETTERS
  doi: 10.1021/acsmedchemlett.9b00256
– volume: 61
  start-page: 9841
  year: 2018
  ident: WOS:000451496300003
  article-title: Biased Ligands of G Protein-Coupled Receptors (GPCRs): Structure-Functional Selectivity Relationships (SFSRs) and Therapeutic Potential
  publication-title: JOURNAL OF MEDICINAL CHEMISTRY
  doi: 10.1021/acs.jmedchem.8b00435
– volume: 11
  start-page: ARTN eaas9609
  year: 2018
  ident: WOS:000438973900003
  article-title: Multisite phosphorylation is required for sustained interaction with GRKs and arrestins during rapid mu-opioid receptor desensitization
  publication-title: SCIENCE SIGNALING
  doi: 10.1126/scisignal.aas9609
– volume: 87
  start-page: 866
  year: 2015
  ident: WOS:000352998500001
  article-title: A Novel Method for Analyzing Extremely Biased Agonism at G Protein-Coupled Receptors
  publication-title: MOLECULAR PHARMACOLOGY
  doi: 10.1124/mol.114.096503
– volume: 13
  start-page: ARTN 54
  year: 2020
  ident: WOS:000534248500001
  article-title: Positive Allosteric Modulation of CB1 Cannabinoid Receptor Signaling Enhances Morphine Antinociception and Attenuates Morphine Tolerance Without Enhancing Morphine- Induced Dependence or Reward
  publication-title: FRONTIERS IN MOLECULAR NEUROSCIENCE
  doi: 10.3389/fnmol.2020.00054
– volume: 113
  start-page: 2110
  year: 2013
  ident: WOS:000322716700002
  article-title: Jaguar: A high-performance quantum chemistry software program with strengths in life and materials sciences
  publication-title: INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY
  doi: 10.1002/qua.24481
– volume: 3
  start-page: 193
  year: 2012
  ident: WOS:000301898000007
  article-title: A Simple Method for Quantifying Functional Selectivity and Agonist Bias
  publication-title: ACS CHEMICAL NEUROSCIENCE
  doi: 10.1021/cn200111m
– volume: 593
  start-page: 281
  year: 2017
  ident: WOS:000414264200014
  article-title: Design and Synthesis of Cannabinoid 1 Receptor (CB1R) Allosteric Modulators: Drug Discovery Applications
  publication-title: CANNABINOIDS AND THEIR RECEPTORS
  doi: 10.1016/bs.mie.2017.06.018
– volume: 95
  start-page: 311
  year: 2017
  ident: WOS:000398837600001
  article-title: Cannabinoid signaling in health and disease
  publication-title: CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY
  doi: 10.1139/cjpp-2016-0346
– volume: 20
  start-page: ARTN 5874
  year: 2019
  ident: WOS:000504428300056
  article-title: Allosteric Modulation of Cannabinoid Receptor 1-Current Challenges and Future Opportunities
  publication-title: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
  doi: 10.3390/ijms20235874
– volume: 63
  start-page: 441
  year: 2020
  ident: WOS:000509438800001
  article-title: The Exploration of Chirality for Improved Druggability within the Human Kinome
  publication-title: JOURNAL OF MEDICINAL CHEMISTRY
  doi: 10.1021/acs.jmedchem.9b00640
– volume: 114
  start-page: 7830
  year: 2010
  ident: WOS:000278479900016
  article-title: Update of the CHARMM All-Atom Additive Force Field for Lipids: Validation on Six Lipid Types
  publication-title: JOURNAL OF PHYSICAL CHEMISTRY B
  doi: 10.1021/jp101759q
– volume: 61
  start-page: 7218
  year: 2018
  ident: WOS:000442960800017
  article-title: Discovery of beta-Arrestin Biased Ligands of 5-HT7R
  publication-title: JOURNAL OF MEDICINAL CHEMISTRY
  doi: 10.1021/acs.jmedchem.8b00642
– volume: 33
  start-page: 187
  year: 1988
  ident: WOS:A1988M150000010
  article-title: ESTIMATION OF THE AFFINITIES OF ALLOSTERIC LIGANDS USING RADIOLIGAND BINDING AND PHARMACOLOGICAL NULL METHODS
  publication-title: MOLECULAR PHARMACOLOGY
– volume: 111
  start-page: 5215
  year: 2011
  ident: WOS:000295542700002
  article-title: The Methylation Effect in Medicinal Chemistry
  publication-title: CHEMICAL REVIEWS
  doi: 10.1021/cr200060g
– volume: 339
  start-page: 757
  year: 2011
  ident: WOS:000297267800003
  article-title: Indirect Sympatholytic Actions at beta-Adrenoceptors Account for the Ocular Hypotensive Actions of Cannabinoid Receptor Agonists
  publication-title: JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
  doi: 10.1124/jpet.111.185769
– volume: 89
  start-page: 364
  year: 2016
  ident: WOS:000370511100004
  article-title: Biased Type 1 Cannabinoid Receptor Signaling Influences Neuronal Viability in a Cell Culture Model of Huntington Disease
  publication-title: MOLECULAR PHARMACOLOGY
  doi: 10.1124/mol.115.101980
– volume: 28
  start-page: 567
  year: 2007
  ident: WOS:000251402900004
  article-title: Allosterism and cannabinoid CB1 receptors: the shape of things to come
  publication-title: TRENDS IN PHARMACOLOGICAL SCIENCES
  doi: 10.1016/j.tips.2007.10.006
– volume: 23
  start-page: 551
  year: 1983
  ident: WOS:A1983QP72800002
  article-title: MODIFICATION OF THE BINDING-PROPERTIES OF MUSCARINIC RECEPTORS BY GALLAMINE
  publication-title: MOLECULAR PHARMACOLOGY
– volume: 109
  start-page: 205
  year: 2011
  ident: WOS:000292511700011
  article-title: Biased Ligands for Better Cardiovascular Drugs Dissecting G-Protein-Coupled Receptor Pharmacology
  publication-title: CIRCULATION RESEARCH
  doi: 10.1161/CIRCRESAHA.110.231308
– volume: 151
  start-page: 1
  year: 2019
  ident: WOS:000468707900001
  article-title: Positive allosteric modulation of the type 1 cannabinoid receptor reduces the signs and symptoms of Huntington's disease in the R6/2 mouse model
  publication-title: NEUROPHARMACOLOGY
  doi: 10.1016/j.neuropharm.2019.03.033
– volume: 285
  start-page: 651
  year: 1998
  ident: WOS:000073585000035
  article-title: Mutation of a highly conserved aspartate residue in the second transmembrane domain of the cannabinoid receptors, CB1 and CB2, disrupts G-protein coupling
  publication-title: JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
– volume: 172
  start-page: 185
  year: 2015
  ident: WOS:000346657300014
  article-title: Biased allosteric modulation at the CaS receptor engendered by structurally diverse calcimimetics
  publication-title: BRITISH JOURNAL OF PHARMACOLOGY
  doi: 10.1111/bph.12937
– volume: 40
  start-page: 2948
  year: 2015
  ident: WOS:000364858200011
  article-title: A Cannabinoid CB1 Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects
  publication-title: NEUROPSYCHOPHARMACOLOGY
  doi: 10.1038/npp.2015.148
– year: 2020
  ident: WOS:000563635600002
  article-title: Positive allosteric modulation of the cannabinoid type-1 receptor (CB1R) in periaqueductal gray (PAG) antagonizes anti-nociceptive and cellular effects of a mu-opioid receptor agonist in morphine-withdrawn rats
  publication-title: PSYCHOPHARMACOLOGY
  doi: 10.1007/s00213-020-05650-5
– volume: 55
  start-page: 4489
  year: 2012
  ident: WOS:000303785900034
  article-title: Methyl Effects on Protein-Ligand Binding
  publication-title: JOURNAL OF MEDICINAL CHEMISTRY
  doi: 10.1021/jm3003697
– year: 1000
  ident: 000668340800012.77
  publication-title: Gaussian 16, revision C. 01
– volume: 43
  start-page: 3216
  year: 2002
  ident: WOS:000178298400012
  article-title: Comparison of the enzymatic stability and intraocular pressure effects of 2-arachidonylglycerol and noladin ether, a novel putative endocannabinoid
  publication-title: INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
– volume: 129
  start-page: 475
  year: 2018
  ident: WOS:000428102600044
  article-title: Enantiomer-specific positive allosteric modulation of CB1 signaling in autaptic hippocampal neurons
  publication-title: PHARMACOLOGICAL RESEARCH
  doi: 10.1016/j.phrs.2017.11.019
– volume: 8
  start-page: 1188
  year: 2017
  ident: WOS:000404098100010
  article-title: Enantiospecific Allosteric Modulation of Cannabinoid 1 Receptor
  publication-title: ACS CHEMICAL NEUROSCIENCE
  doi: 10.1021/acschemneuro.6b00310
– reference: 34019766 - J Med Chem. 2021 Jun 24;64(12):8101-8103
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Snippet We apply the magic methyl effect to improve the potency/efficacy of GAT211, the prototypic 2-phenylindole-based cannabinoid type-1 receptor (CB1R)...
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SubjectTerms Allosteric Site
Animals
Cannabinoid Receptor Agonists - chemical synthesis
Cannabinoid Receptor Agonists - metabolism
Cannabinoid Receptor Agonists - therapeutic use
Chemistry, Medicinal
CHO Cells
Cricetulus
Glaucoma - drug therapy
HEK293 Cells
Hippocampus - cytology
Humans
Indoles - chemical synthesis
Indoles - metabolism
Indoles - therapeutic use
Intraocular Pressure - drug effects
Life Sciences & Biomedicine
Ligands
Male
Mice
Mice, Inbred C57BL
Molecular Conformation
Molecular Docking Simulation
Molecular Dynamics Simulation
Neurons - drug effects
Pharmacology & Pharmacy
Receptor, Cannabinoid, CB1 - agonists
Receptor, Cannabinoid, CB1 - chemistry
Receptor, Cannabinoid, CB1 - metabolism
Science & Technology
Stereoisomerism
Structure-Activity Relationship
Title Discovery of a Biased Allosteric Modulator for Cannabinoid 1 Receptor: Preclinical Anti-Glaucoma Efficacy
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