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

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• 作者：Amey Sadashiv Dhopeshwarkar ; Russell Alfred Nicholson
• 关键词：Benzophenanthridine alkaloid ; Piperonyl butoxide ; (S)-methoprene ; CB1 receptor ; [³ ; H]CP55940 ; [³ ; H]SR141716A ; [35S]GTP纬S ; 4-AP ; l-glutamate ; Synaptosome
• 刊名：European Journal of Pharmacology
• 出版年：15 January, 2014
• 年：2014
• 卷：723
• 期：Complete
• 页码：431-441
• 全文大小：1653 K

文摘

Benzophenanthridine alkaloids (chelerythrine and sanguinarine) inhibited binding of [³H]SR141716A to mouse brain membranes (IC₅₀s: <1 碌M). Piperonyl butoxide and (S)-methoprene were less potent (IC₅₀s: 21 and 63 碌M respectively). Benzophenanthridines and piperonyl butoxide were more selective towards brain CB₁ receptors versus spleen CB₂ receptors. All compounds reduced B_max of [³H]SR141716A binding to CB₁ receptors, but only methoprene and piperonyl butoxide increased K_d (3-5-fold). Benzophenanthridines increased the K_d of [³H]CP55940 binding (6-fold), but did not alter B_max. (S)-methoprene increased the K_d of [³H]CP55940 binding (by almost 4-fold) and reduced B_max by 60%. Piperonyl butoxide lowered the B_max of [³H]CP55940 binding by 50%, but did not influence K_d. 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]GTP纬S 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.