title: The importance of the 6- and 7-positions of tetrahydroisoquinolines as selective antagonists for the orexin 1 receptor.
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 (10 c, Ke = 23.7 nM). While the 6-substituted analogs were generally inactive, several 6-amino compounds bearing ester groups showed reasonable potency (26 a, Ke = 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.
authors.affiliation: Research Triangle Institute, Research Triangle Park, NC 27709, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Perrey
authors.affiliation: Research Triangle Institute, Research Triangle Park, NC 27709, United States.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Decker
authors.affiliation: Department of Pharmacology and Toxicology, University at Buffalo, The State University of New York, Buffalo, NY 14214, United States.
authors.forename: Jun-Xu
authors.initials: JX
authors.lastname: Li
authors.affiliation: Research Triangle Institute, Research Triangle Park, NC 27709, United States.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Gilmour
authors.affiliation: Research Triangle Institute, Research Triangle Park, NC 27709, United States.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Thomas
authors.affiliation: Research Triangle Institute, Research Triangle Park, NC 27709, United States.
authors.forename: Danni L
authors.initials: DL
authors.lastname: Harris
authors.affiliation: Research Triangle Institute, Research Triangle Park, NC 27709, United States.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Runyon
authors.affiliation: Research Triangle Institute, Research Triangle Park, NC 27709, United States. Electronic address: yzhang@rti.org.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D006801:Humans; D015394:Molecular Structure; D000068797:Orexins / Q000235:genetics*; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000378:metabolism*
chemical_list: D000068797:Orexins; D044005:Tetrahydroisoquinolines
keywords: Antagonist; Orexin; Selective; Tetrahydroisoquinoline