Abstract | BACKGROUND AND PURPOSE: EXPERIMENTAL APPROACH: The pharmacological properties of the 8-methylquinolines as exemplified by MQ1 were evaluated by use of multiple biophysical and cell-based functional assays. KEY RESULTS: Multiple signalling pathways for Gαi and Gαq , and β- arrestin were inhibited by MQ1. Furthermore, MQ1 produced an insurmountable antagonism, causing a rightward shift of the curve for concentration-dependent binding of MCH along with a progressive reduction of the maximal response. The dissociation kinetics for MQ1 were determined from washout experiments as well as by affinity selection-MS. In short, MQ1 was shown to be a slowly dissociating reversible MCH1 receptor blocker with a low Koff value. CONCLUSION AND IMPLICATIONS: This is the first time that a slowly dissociating negative allosteric modulator of the MCH1 receptor has been demonstrated to inhibit the numerous signalling pathways of this receptor. The characteristics of MQ1 are superior and distinct from previously reported MCH1 receptor antagonists, making members of this chemotype attractive as drug candidates.
|
Authors | T Sakurai, K Ogawa, Y Ishihara, S Kasai, M Nakayama |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 171
Issue 5
Pg. 1287-98
(Mar 2014)
ISSN: 1476-5381 [Electronic] England |
PMID | 24670150
(Publication Type: Journal Article)
|
Copyright | © 2013 The British Pharmacological Society. |
Chemical References |
- 4-(cyclopropylmethoxy)-N-(8-methyl-3-(1-(pyrrolidin-1-yl)ethyl)quinolin-7-yl)benzamide
- Anti-Obesity Agents
- Benzamides
- MCHR1 protein, human
- Quinolines
- Receptors, Somatostatin
- 8-methylquinoline
|
Topics |
- Allosteric Regulation
- Animals
- Anti-Obesity Agents
(pharmacology)
- Benzamides
(pharmacology)
- CHO Cells
- Cricetulus
- Humans
- Quinolines
(pharmacology)
- Receptors, Somatostatin
(antagonists & inhibitors, genetics, metabolism)
|