Synthesis and structure-affinity relationship investigations of 5-aminomethyl and 5-carbamoyl analogues of the antipsychotic sertindole. A new class of selective alpha1 adrenoceptor antagonists |
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Authors: | Balle Thomas Perregaard Jens Larsen Anna K Ramirez Martha Teresa Krøjer Søby Karina Liljefors Tommy Andersen Kim |
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Institution: | Medicinal Chemistry Research, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark. |
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Abstract: | A new class of selective alpha(1) adrenoceptor antagonists derived from the antipsychotic drug sertindole is described. The most potent and selective compound 1-(2-(4-5-aminomethyl-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl)ethyl)-2-imidazolidinone (11) binds with 0.50 nM affinity for alpha(1) adrenergic receptors and with more than 44 times lower affinity for dopamine D(2),D(3), D(4) and serotonin 5-HT(1A), 5-HT(1B), 5-HT(2A) and 5-HT(2C) receptors. The molecular features providing high affinity for adrenergic alpha(1) receptors and high selectivity towards dopamine D(2) and serotonin 5-HT(2A) and 5-HT(2C) receptors are discussed. |
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