title: Effect of 1-substitution on tetrahydroisoquinolines as selective antagonists for the orexin-1 receptor.
abstract: Selective blockade of the orexin-1 receptor (OX1) has been suggested as a potential approach to drug addiction therapy because of its role in modulating the brain's reward system. We have recently reported a series of tetrahydroisoquinoline-based OX1 selective antagonists. Aimed at elucidating structure-activity relationship requirements in other regions of the molecule and further enhancing OX1 potency and selectivity, we have designed and synthesized a series of analogues bearing a variety of substituents at the 1-position of the tetrahydroisoquinoline. The results show that an optimally substituted benzyl group is required for activity at the OX1 receptor. Several compounds with improved potency and/or selectivity have been identified. When combined with structural modifications that were previously found to improve selectivity, we have identified compound 73 (RTIOX-251) with an apparent dissociation constant (Ke) of 16.1 nM at the OX1 receptor and >620-fold selectivity over the OX2 receptor. In vivo, compound 73 was shown to block the development of locomotor sensitization to cocaine in rats.
authors: †Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States.
authors: David A
authors: DA
authors: Perrey
authors: †Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States.
authors: Nadezhda A
authors: NA
authors: German
authors: †Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States.
authors: Ann M
authors: AM
authors: Decker
authors: ‡Department of Pharmacology and Toxicology, University at Buffalo, the State University of New York, Buffalo, New York 14214, United States.
authors: David
authors: D
authors: Thorn
authors: ‡Department of Pharmacology and Toxicology, University at Buffalo, the State University of New York, Buffalo, New York 14214, United States.
authors: Jun-Xu
authors: JX
authors: Li
authors: †Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States.
authors: Brian P
authors: BP
authors: Gilmour
authors: †Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States.
authors: Brian F
authors: BF
authors: Thomas
authors: †Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States.
authors: Danni L
authors: DL
authors: Harris
authors: †Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States.
authors: Scott P
authors: SP
authors: Runyon
authors: †Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States.
authors: Yanan
authors: Y
authors: Zhang
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology; D003412:Cricetulus; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D015394:Molecular Structure; D000068796:Orexin Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D064446:Orexin Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D018765:Dopamine Uptake Inhibitors; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D044005:Tetrahydroisoquinolines; D003042:Cocaine; D002118:Calcium
keywords: Orexin; antagonist; selective; tetrahydroisoquinoline
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