title: Aiming for allosterism: Evaluation of allosteric modulators of CB1 in a neuronal model.
abstract: Cannabinoid pharmacology has proven nettlesome with issues of promiscuity a common theme among both agonists and antagonists. One recourse is to develop allosteric ligands to modulate cannabinoid receptor signaling. Cannabinoids have come late to the allosteric table. The 'first-generation' negative and positive allosteric modulators (NAMs and PAMs) represent an important first effort. However, most studies have relied on synthetic agonists, often tested in over-expression systems rather than a defined neuronal model system that utilizes endogenously synthesized and released cannabinoids. We have systematically examined first-generation NAMs and a PAM on endocannabinoid modulation of synaptic transmission in cultured autaptic hippocampal neurons. These neurons exhibit CB1 and 2-arachidonoyl glycerol (2-AG)-mediated depolarization induced suppression of excitation (DSE) and therefore serve as a model to test CB1 modulators in a neuronal model of endogenous cannabinoid signaling. We find ORG27569, PSNCBAM-1, and PEPCAN12 attenuate DSE and do not directly inhibit CB1 receptors. Of these PSNCBAM-1 is the most efficacious while PEPCAN12 has the distinction of being an endogenous NAM. The reported NAMs pregnenolone and hemopressin as well as the reported PAM lipoxin A4 are without effect in this model of endocannabinoid signaling. In summary, three of the allosteric modulators evaluated function in a manner consistent with allosterism in a neuronal 2-AG-based model of endogenous cannabinoid signaling.
authors.affiliation: Department of Psychological and Brain Sciences, Gill Center for Biomolecular Science, Indiana University, 1101 E, 10th St, Bloomington, IN 47405, United States. Electronic address: straiker@indiana.edu.
authors.forename: Alex
authors.initials: A
authors.lastname: Straiker
authors.affiliation: Department of Psychological and Brain Sciences, Gill Center for Biomolecular Science, Indiana University, 1101 E, 10th St, Bloomington, IN 47405, United States.
authors.forename: José
authors.initials: J
authors.lastname: Mitjavila
authors.affiliation: Department of Psychological and Brain Sciences, Gill Center for Biomolecular Science, Indiana University, 1101 E, 10th St, Bloomington, IN 47405, United States.
authors.forename: Danielle
authors.initials: D
authors.lastname: Yin
authors.affiliation: Department of Psychological and Brain Sciences, Gill Center for Biomolecular Science, Indiana University, 1101 E, 10th St, Bloomington, IN 47405, United States.
authors.forename: Anne
authors.initials: A
authors.lastname: Gibson
authors.affiliation: Department of Psychological and Brain Sciences, Gill Center for Biomolecular Science, Indiana University, 1101 E, 10th St, Bloomington, IN 47405, United States.
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology; D063388:Endocannabinoids / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005989:Glycerides / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: C526691:1-(4-chlorophenyl)-3-(3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl)urea; C572504:5-chloro-3-ethyl-1H-indole-2-carboxylic acid (2-(4-piperidin-1-yl-phenyl)ethyl)amide; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D005989:Glycerides; D007211:Indoles; D010671:Phenylurea Compounds; D010880:Piperidines; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; C094503:glyceryl 2-arachidonate
keywords: Allosteric; Allosterism; Cannabinoid; Depolarization-induced suppression of excitation; Excitatory postsynaptic current; Orthosteric; Tetrahydrocannabinol