Novel 2(3H)-Benzothiazolones as Highly Potent and Selective Sigma-1 Receptor Ligands |
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| Authors: | Saïd Yous Valérie Wallez Mirabelle Belloir Daniel H Caignard Christopher R McCurdy Jacques H Poupaert |
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| Institution: | (1) Laboratoire de Chimie Thérapeutique, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Lille 2. 3, rue du Professeur Laguesse, F-59006 Lille Cedex, France, BP 83;(2) ADIR et Cie, 1 rue Carle Hébert, F-92415 Courbevoie, France;(3) Laboratory for Applied Drug Design and Synthesis, Department of Medicinal Chemistry, School of Pharmacy, The University of Mississippi, University, MS USA, 38677;(4) Unité de Chimie Pharmaceutique, Ecole de Pharmacie, Faculté de Médecine, Université Catholique de Louvain, B-1200 Bruxelles, Belgium |
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| Abstract: | In an effort to produce a new pharmacological probe with high affinity and selectivity for the sigma-1 receptor, we have synthesized
a series of original 2(3H)-benzothiazolones utilizing compound 4 3-(1-piperidinoethyl)-6-propylbenzothiazolin-2-one] as a lead. Receptor binding affinities were determined at sigma-1 and
sigma-2 receptors. The best ligand (9, sigma-1 Ki = 0.56 nM, selectivity ratio >1000) was obtained with an azepine side-chain. When tested on a wide battery of receptors,
including 5HT2A(h), 5HT3(h), α1, α 2, β1, β2, H1, H2, opioids, D1(h), D2(h), 5HT uptake, and DOPA uptake, compound 9 showed submicromolar affinity only for α2 (Ki = 205 nM) and H1 (Ki = 311 nM). |
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