Journal ArticleDOI
Conformationally restrained analogues of pravadoline: nanomolar potent, enantioselective, (aminoalkyl)indole agonists of the cannabinoid receptor.
Thomas E. D'Ambra,Estep Kg,Malcolm R. Bell,Eissenstat Ma,Kurt A. Josef,Susan Jean Ward,Haycock Da,Baizman Er,F. M. Casiano,Beglin Nc +9 more
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TLDR
Binding studies with this ligand have helped demonstrate that the (aminoalkyl)indole binding site is functionally equivalent with the CP-55,940 cannabinoid binding site, representing a new class of cannabinoid receptor agonists.Abstract:
Pravadoline (1) is an (aminoalkyl)indole analgesic agent which is an inhibitor of cyclooxygenase and, in contrast to other NSAIDs, inhibits neuronally stimulated contractions in mouse vas deferens (MVD) preparations (IC50 = 0.45 microM). A number of conformationally restrained heterocyclic analogues of pravadoline were synthesized in which the morpholinoethyl side chain was tethered to the indole nucleus. Restraining the morpholine diminished the ability of these pravadoline analogues to inhibit prostaglandin synthesis in vitro. In contrast, mouse vas deferens inhibitory activity was enhanced in [2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl] pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-(4-methoxyphenyl)methano ne (20). Only the R enantiomer of 20 was active (IC50 = 0.044 microM). An optimal orientation of the morpholine nitrogen for MVD inhibitory activity within the analogues studied was in the lower right quadrant, below the plane defined by the indole ring. A subseries of analogues of 20 and a radioligand of the most potent analogue, (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo [1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthalenyl)methanone (21) were prepared. Inhibition of radioligand binding in rat cerebellar membranes was observed to correlate with functional activity in mouse vas deferens preparations. Binding studies with this ligand (Win 55212-2) have helped demonstrate that the (aminoalkyl)indole binding site is functionally equivalent with the CP-55,940 cannabinoid binding site. These compounds represent a new class of cannabinoid receptor agonists.read more
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International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors
Allyn C. Howlett,Francis Barth,Tom I. Bonner,Guy A. Cabral,Pierre Casellas,William A. Devane,Christian C. Felder,Miles Herkenham,Ken Mackie,Billy R. Martin,Raphael Mechoulam,Roger G. Pertwee +11 more
TL;DR: It is considered premature to rename cannabinoid receptors after an endogenous agonist as is recommended by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification, because pharmacological evidence for the existence of additional types of cannabinoid receptor is emerging and other kinds of supporting evidence are still lacking.
Journal ArticleDOI
SR141716A, a potent and selective antagonist of the brain cannabinoid receptor
Murielle Rinaldi-Carmona,Francis Barth,Michel Heaulme,David Shire,Bernard Calandra,Christian Congy,Serge Martinez,Jeanne Maruani,Gervais Neliat,Daniel Caput,P. Ferrara,Philippe Soubrie,J. C. Breliere,Gérard Le Fur +13 more
TL;DR: SR141716A is the first selective and orally active antagonist of the brain cannabinoid receptor and should prove to be a powerful tool for investigating the in vivo functions of the anandamide/cannabinoid system.
Journal ArticleDOI
Role of Endogenous Cannabinoids in Synaptic Signaling
TL;DR: The synthetic pathways of endocannabinoids are discussed, along with the putative mechanisms of their release, uptake, and degradation, and the fine-grain anatomical distribution of the neuronal cannabinoid receptor CB1 is described in most brain areas, emphasizing its general presynaptic localization and role in controlling neurotransmitter release.
Journal ArticleDOI
Presynaptically Located CB1 Cannabinoid Receptors Regulate GABA Release from Axon Terminals of Specific Hippocampal Interneurons
István Katona,Beáta Sperlágh,Attila Sik,Attila Käfalvi,E. Sylvester Vizi,Ken Mackie,Tamás F. Freund +6 more
TL;DR: The results suggest that cannabinoid-mediated modulation of hippocampal interneuron networks operate largely via presynaptic receptors on CCK-immunoreactive basket cell terminals, the likely mechanism by which both endogenous and exogenous CB1 ligands interfere with hippocampal network oscillations and associated cognitive functions.
Journal Article
SR 144528, the First Potent and Selective Antagonist of the CB2 Cannabinoid Receptor
Murielle Rinaldi-Carmona,Francis Barth,Millan J,Jean-Marie Derocq,P. Casellas,Christian Congy,Didier Oustric,Sarran M,Monsif Bouaboula,Bernard Calandra,Marielle Portier,David Shire,J. C. Breliere,Le Fur Gl +13 more
TL;DR: It is expected that SR 144528 will provide a powerful tool to investigate the in vivo functions of the cannabinoid system in the immune response.