RESUMO
Conformational restriction of naftopidil proved to be compatible with binding at alpha(1) adrenoceptor subtypes and 5-HT receptor 1A (5-HT(1A)), and led to the discovery of a new class of ligands with a 1,3-dioxolane (1,3-oxathiolane, 1,3-dithiolane) structure. Compound 7 shows the highest affinity toward alpha(1a) and alpha(1d) adrenoceptor subtypes (pK(i) alpha(1a) = 9.58, pK(i) alpha(1d) = 9.09) and selectivity over 5-HT(1A) receptors (alpha(1a)/5-HT(1A) = 100, alpha(1d)/5-HT(1A) = 26). In functional experiments it behaves as a potent competitive alpha(1a) and alpha(1d) adrenoceptor antagonist (pK(b) alpha(1A) = 8.24, pK(b) alpha(1D) = 8.14), whereas at 5-HT(1A) receptors it is a potent partial agonist (pD(2) = 8.30). Compounds 8 and 10 display high affinity (pK(i) = 8.29 and 8.26, respectively) and selectivity for 5-HT(1A) (5-HT(1A)/alpha(1) = 18 and 10). In functional experiments at the 5-HT(1A) receptor, compound 8 appears to be neutral antagonist (pK(b) = 7.29), whereas compound 10 is a partial agonist (pD(2) = 6.27). Therefore, 1,3-dioxolane-based ligands are a versatile class of compounds useful for the development of more selective ligands for one (alpha(1)) or the other (5-HT(1A)) receptor system.
Assuntos
Antagonistas Adrenérgicos alfa/síntese química , Antagonistas Adrenérgicos alfa/farmacologia , Dioxolanos/síntese química , Dioxolanos/farmacologia , Naftalenos/síntese química , Naftalenos/farmacologia , Piperazinas/síntese química , Piperazinas/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Receptores Adrenérgicos alfa/metabolismo , Antagonistas Adrenérgicos alfa/química , Animais , Dioxolanos/química , Células HeLa , Humanos , Ligantes , Masculino , Naftalenos/química , Piperazinas/química , Ligação Proteica , Ratos , Ratos Wistar , Agonistas do Receptor 5-HT1 de Serotonina , Antagonistas do Receptor 5-HT1 de Serotonina , Relação Estrutura-AtividadeRESUMO
Starting from compound 1, a previously reported alpha(1D)-adrenoceptors antagonist, a new series of ligands acting at 5-HT(1A) serotonin receptor were identified through simple structure modifications. Among them (2,2-diphenyl-[1,3]oxathiolan-5-yl-methyl)-(3-phenyl-propyl)amine (19) exhibits outstanding activity (pK(i)=8.72, pD(2)=7.67, E(max)=85) and selectivity (5-HT(1A)/alpha(1D)>150), and represents an as yet unidentified 5-HT(1A) agonist scaffold.
