Substituted hexahydrobenzo[f]thieno[c]quinolines as dopamine D1-selective agonists: synthesis and biological evaluation in vitro and in vivo

Journal of Medicinal Chemistry
M MichaelidesK Shiosaki

Abstract

A series of substituted 9,10-dihydroxyhexahydrobenzo[f]thieno[c]quinolines (TB[f]Q), varying with respect to the position of the thiophene relative to the benzo[f]quinoline core and the nature and position of the substituent on the thiophene, were prepared and evaluated for their affinity and selectivity for the dopamine D1-like receptor. The thieno[3,2-c]B[f]Q regioisomers bearing a small alky1 (C1-C3) substituent at the 2 position were potent (Ki < 20 nM) and selective (D2/D1 > 50) D1 agonists with close to full agonist activity (IA > 85%). The compounds were resolved and found to exhibit a high level of enantiospecificity in their interaction with the D1 receptor. Selected compounds were tested in vivo in the 6-OHDA rodent model of Parkinson's disease and for their liability to produce seizure-like activities in mice. (5aR)-trans-2-Propyl-4,5,5a,6,7, 11b-hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene-9,10-diol (5) emerged as the compound with the best overall in vivo profile in terms of potency (ED50 = 0.04 mumol/kg) and safety.

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Citations

Apr 1, 2006·Psychopharmacology·Scott D Gleason, Jeffrey M Witkin
Feb 5, 2004·Bioorganic & Medicinal Chemistry·Sing-Yuen SitRichard B Mailman
Apr 28, 2011·Acta Crystallographica. Section E, Structure Reports Online·Roman LytvynVasyl Kinzhybalo
Apr 14, 2017·Journal of the American Chemical Society·Brian P WoodsAbigail G Doyle
Jun 14, 2014·Organic & Biomolecular Chemistry·Anna K WeberAxel Jacobi von Wangelin
Apr 13, 2004·Behavioural Pharmacology·S D Gleason, J M Witkin
Nov 3, 2020·Chemistry : a European Journal·Glwadys GagnotYves L Janin
May 13, 2004·Chemical Reviews·Rafael ChinchillaMiguel Yus

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