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.
journal_name
Pharmacol Resjournal_title
Pharmacological researchauthors
Lin Y,Shia KS,Hsiao WC,Hsieh WP,Yeh TK,Tseng SL,Hsu CY,Chao YS,Hung MSdoi
10.1016/j.phrs.2010.06.001subject
Has Abstractpub_date
2010-10-01 00:00:00pages
337-43issue
4eissn
1043-6618issn
1096-1186pii
S1043-6618(10)00124-6journal_volume
62pub_type
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