138645-09-7Relevant articles and documents
Effect of 1-Substitution on Tetrahydroisoquinolines as Selective Antagonists for the Orexin-1 Receptor
Perrey, David A.,German, Nadezhda A.,Decker, Ann M.,Thorn, David,Li, Jun-Xu,Gilmour, Brian P.,Thomas, Brian F.,Harris, Danni L.,Runyon, Scott P.,Zhang, Yanan
, p. 599 - 614 (2015/04/27)
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. (Chemical Equation Presented).
Mammalian alkaloids: Synthesis and O-methylation of (S)- and (R)-3'-hydroxycoclaurine and their N-methylated analogues with S-adenosyl-L-[methyl-14C]methionine in presence of mammalian catechol O-methyltransferase
He,Tadic,Brzostowska,Brossi,Bell,Creveling
, p. 1399 - 1411 (2007/10/02)
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