The importance of the 6- and 7-positions of tetrahydroisoquinolines as selective antagonists for the orexin 1 receptor. Issue 17 (1st September 2015)

• Record Type: Journal Article
• Authors: Perrey, David A.; Decker, Ann M.; Li, Jun-Xu; Gilmour, Brian P.; Thomas, Brian F.; Harris, Danni L.; Runyon, Scott P.; Zhang, Yanan
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 17(2015)
• Page Start: 5709
• Page End: 5724
• Publication Date: 2015-09-01
• Subjects: BOP (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate -- HATU 1-[bis(dimethylamino)methylene]-1H-1, 2, 3-triazolo[4, 5-b]pyridinium 3-oxid hexafluorophosphate -- HPLC high performance liquid chromatography -- OX1 orexin 1 receptor -- OX2 orexin 2 receptor -- SAR structure–activity relationship -- TLC thin layer chromatography; Orexin -- Antagonist -- Selective -- Tetrahydroisoquinoline; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.07.013
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Selective antagonism of the orexin 1 (OX1 ) receptor has been proposed as a potential mechanism for treatment of drug addiction. We have previously reported studies on the structure–activity relationships of tetrahydroisoquinoline-based antagonists. In this report, we elucidated the respective role of the 6- and 7-substitutions by preparation of a series of either 6-substituted tetrahydroisoquinolines (with no 7-substituents) or vice versa. We found that 7-substituted tetrahydroisoquinolines showed potent antagonism of OX1, indicating that the 7-position is important for OX1 antagonism (10c, K e = 23.7 nM). While the 6-substituted analogs were generally inactive, several 6-amino compounds bearing ester groups showed reasonable potency (26a, K e = 427 nM). Further, we show evidence that suggests several compounds initially displaying insurmountable antagonism at the OX1 receptor are competitive antagonists with slow dissociation rates.