Synthesis and structure-affinity relationship investigations of 5-heteroaryl-substituted analogues of the antipsychotic sertindole.: A new class of highly selective α1 adrenoceptor antagonists

A new class of 5-heteroaryl-substituted 1-(4-fluorophenyl)-3-(4-piperidinyl)-1H-indoles as highly selective and potentially CNS-active alpha(1)-adrenoceptor antagonists is described. The compounds are derived from the antipsychotic sertindole. The structure-affinity relationships of the 5-heteroaryl substituents, and the substituents on the piperidine nitrogen atom were optimized with respect to affinity for alpha(1) adrenoceptors and selectivity in respect to dopamine (D1-4) and serotonin (5-HT1A-1B and 5-HT2A,2C) receptors. The most selective compound obtained, 3-{4-[1-(4-fluorophenyl)-5-(1-methyl-1,2,4-triazol-3-yl)-1H-indol-3-yl]-1-piperidinyl}propionitrile (15c), has affinities of 0.99, 3.2, and 9.0 nM for the alpha(1a), alpha(1b), and alpha(1d) adrenoceptor subtypes, respectively, and a selectivity for adrenergic alpha(1a) receptors in respect to dopamine D-2, D-3, and D-4 and serotonin 5-HT2A and 5-HT2C higher than 900, comparable to the selectivity of prazosin. In addition, the compound is more than 150-fold selective in respect to serotonin 5-HT1A and 5-HT1B receptors. A new basic pharmacophore for alpha(1)-adrenoceptor antagonists based on a previously reported pharmacophore model for dopamine D-2 antagonist is suggested.