title: Biphasic suppression of appetite by cannabinoid CB1 receptor antagonists with distinct functional activities.
abstract: A novel alkynylthiophene series of cannabinoid CB1 receptor antagonists has been described to exhibit distinct intrinsic activities with minimal substructure modifications. The three representatives, BPR0432, BPR0568 and BPR0569, functioning as a neutral antagonist, an inverse agonist and a partial agonist, respectively, in GTP binding assay, were further characterized for their downstream signaling activities in relation to in vivo efficacy in appetite suppression to diets of different macronutrients. Interestingly, these three derivatives all behaved as inverse agonists with the potency of BPR0432>BPR0568>BPR0569 in cAMP assay. After administered to non-deprived rats, the potency in appetite suppression was positively related to their strength in intrinsic activity in the first hour of intake. The preferential suppression to high fat and high carbohydrate diets was revealed after 6h and only appeared in the treatment of BPR0568, presumably due to its metabolic stability in addition to its intrinsic activity. These results indicated the suppression of appetite was controlled in a biphasic manner, and these three structurally close but functionally distinct compounds are invaluable tools in elucidating the mechanism of neuronal response to appetite and palatability.
authors.affiliation: Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Yinchiu
authors.initials: Y
authors.lastname: Lin
authors.forename: Kak-Shan
authors.initials: KS
authors.lastname: Shia
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Hsiao
authors.forename: Wan-Ping
authors.initials: WP
authors.lastname: Hsieh
authors.forename: Teng-Kuang
authors.initials: TK
authors.lastname: Yeh
authors.forename: Shi-Liang
authors.initials: SL
authors.lastname: Tseng
authors.forename: Chia-Yu
authors.initials: CY
authors.lastname: Hsu
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.forename: Ming-Shiu
authors.initials: MS
authors.lastname: Hung
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D001066:Appetite / Q000187:drug effects*; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D002149:Energy Intake / Q000187:drug effects; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013876:Thiophenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D019440:Anti-Obesity Agents; D043884:Receptor, Cannabinoid, CB1; D013876:Thiophenes; D000242:Cyclic AMP