Benzophenanthridine alkaloid, piperonyl butoxide and (S)-methoprene action at the cannabinoid-1 receptor (CB1-receptor) pathway of mouse brain: Interference with [3H]CP55940 and [3H]SR141716A binding and modification of WIN55212-2-dependent inhibition of synaptosomal l-glutamate release

Benzophenanthridine alkaloids (chelerythrine and sanguinarine) inhibited binding of [3H]SR141716A to mouse brain membranes (IC50s: <1µM). Piperonyl butoxide and (S)-methoprene were less potent (IC50s: 21 and 63µM respectively). Benzophenanthridines and piperonyl butoxide were more selective towar...

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Bibliographic Details
Published in:	European journal of pharmacology Vol. 723; pp. 431 - 441
Main Authors:	Dhopeshwarkar, Amey Sadashiv, Nicholson, Russell Alfred
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 15-01-2014
Subjects:	(S)-methoprene 4-AP [35S]GTPγS [³H]CP55940 [³H]SR141716A Animals Benzophenanthridine alkaloid Benzophenanthridines - pharmacology Benzoxazines - pharmacology Binding Sites Brain - metabolism CB1 receptor Cyclohexanols - pharmacology Glutamic Acid - metabolism Isoquinolines - pharmacology l-glutamate Male Methoprene - pharmacology Mice Morpholines - pharmacology Naphthalenes - pharmacology Piperidines - pharmacology Piperonyl butoxide Piperonyl Butoxide - pharmacology Pyrazoles - pharmacology Radioligand Assay Receptor, Cannabinoid, CB1 - metabolism Receptor, Cannabinoid, CB2 - metabolism Rimonabant Spleen - metabolism Synaptosome Synaptosomes - metabolism [³H]CP55940 4-AP l-glutamate Synaptosome [³H]SR141716A CB1 receptor Benzophenanthridine alkaloid Piperonyl butoxide (S)-methoprene [35S]GTPγS
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Summary:	Benzophenanthridine alkaloids (chelerythrine and sanguinarine) inhibited binding of [3H]SR141716A to mouse brain membranes (IC50s: <1µM). Piperonyl butoxide and (S)-methoprene were less potent (IC50s: 21 and 63µM respectively). Benzophenanthridines and piperonyl butoxide were more selective towards brain CB1 receptors versus spleen CB2 receptors. All compounds reduced Bmax of [3H]SR141716A binding to CB1 receptors, but only methoprene and piperonyl butoxide increased Kd (3–5-fold). Benzophenanthridines increased the Kd of [3H]CP55940 binding (6-fold), but did not alter Bmax. (S)-methoprene increased the Kd of [3H]CP55940 binding (by almost 4-fold) and reduced Bmax by 60%. Piperonyl butoxide lowered the Bmax of [3H]CP55940 binding by 50%, but did not influence Kd. All compounds reduced [3H]SR141716A and [3H]CP55940 association with CB1 receptors. Combined with a saturating concentration of SR141716A, only piperonyl butoxide and (S)-methoprene increased dissociation of [3H]SR141716A above that of SR141716A alone. Only piperonyl butoxide increased dissociation of [3H]CP55940 to a level greater than CP55940 alone. Binding results indicate predominantly allosteric components to the study compounds action. 4-Aminopyridine-(4-AP-) evoked release of l-glutamate from synaptosomes was partially inhibited by WIN55212-2, an effect completely neutralized by AM251, (S)-methoprene and piperonyl butoxide. With WIN55212-2 present, benzophenanthridines enhanced 4-AP-evoked l-glutamate release above 4-AP alone. Modulatory patterns of l-glutamate release (with WIN-55212-2 present) align with previous antagonist/inverse agonist profiling based on [35S]GTPγS binding. Although these compounds exhibit lower potencies compared to many classical CB1 receptor inhibitors, they may have potential to modify CB1-receptor-dependent behavioral/physiological outcomes in the whole animal.
ISSN:	0014-2999 1879-0712
DOI:	10.1016/j.ejphar.2013.10.059