[1,2,4]Triazole derivatives as 5-HT1A serotonin receptor ligands Original Research Article

A series of new 4-amino-3-[3-[4-(2-methoxy or nitro phenyl)-1-piperazinyl] propyl]thio]-5-(substitutedphenyl)[1,2,4]triazoles 11a–t was synthesized in order to obtain compounds with high affinity and selectivity for 5-HT1A receptor over the α1-adrenoceptor. A series of isomeric 4-amino-2-[3-[4-(2-methoxy or nitro phenyl)-1-piperazinyl]propyl]-5-(substitutedphenyl)-2,4-dihydro-3H[1,2,4]triazole-3-thiones 12a–r was also isolated and characterized. New compounds were tested to evaluate their affinity for 5-HT1A receptor and α1-adrenoceptor in radioligand binding experiments. As a general trend, triazoles 11a–t showed a preferential affinity for the 5-HT1A receptor whereas isomeric 2,4-dihydro-3H[1,2,4]triazole-3-thiones 12a–r preferentially bind to the α1-adrenoceptor site. Several molecules showed affinities in the nanomolar range and 4-amino-3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-5-(4-propyloxy-phenyl)[1,2,4]triazole (11o) was the most selective derivative for the 5-HT1A receptor (Ki α1/Ki 5-HT1A=55). The decrease in 5-HT1A receptor selectivity in 3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-5-(substitutedphenyl)[1,2,4] triazole 14a–b, lacking in the amino group in 4-position of the triazole ring, in comparison with their analogues in the series 11a–t, suggest that the amino function represents a critical structural feature in determining 5-HT1A receptor selectivity in this class of compounds.