Synthesis of new 5-phenyl[1,2,4]triazole derivatives as ligands for the 5-HT1A serotonin receptor

Synthesis of New Arylpiperazinylalkylthiobenzimidazole, Benzothiazole, or Benzoxazole Derivatives as Potent and Selective 5-HT1A Serotonin Receptor Ligands

“…The first step of our investigation was the synthesis of compounds 16 − 27 in which a 2-methoxy- or a 2-nitrophenylpiperazine was linked to a benzoxazole, benzothiazole, or benzimidazole system by an ethylthio or propylthio unit. In general, derivatives 19 − 21 and 25 − 27 , which possess the 2-nitrophenylpiperazine, showed lower affinity for 5-HT 1A R with respect to the 2-methoxyphenylpiperazine analogues 16 − 18 and 22 − 24 , as previously described for analogues containing 5-phenyl[1,2,4]triazole nucleus. , In addition, compounds characterized by a thiopropyl chain between the terminal fragment and the arylpiperazine portion ( 22 − 27 ) exhibited higher affinity toward 5-HT 1A R with respect to the analogues 16 − 21 containing a thioethyl chain as linker. In particular, among thiopropyl derivatives, 23 was the most interesting because it showed an affinity for 5-HT 1A R in the subnanomolar range ( K i = 0.29 nM) coupled to a high selectivity over α 1 -AR ( K i α 1 -AR/ K i 5-HT 1A R = 114).…”

“…Among them, thieno[2,3- d ]pyrimidine derivatives 3 and 4 (Chart ) showed high affinity for the 5-HT 1A R coupled to a reduced affinity for α 1 -AR. More recently, we reported structure−affinity relationship (SAR) studies on a class of 5-phenyl[1,2,4]triazoles structurally related to 3 and 4 , in which the aryl[1,2,4]triazole replaced the 3-amino-6-ethylthieno[2,3- d ]pyrimidin-4(3 H )-one moiety. , Some of these compounds showed K i values in the nanomolar range, in particular, compound 5 exhibited good selectivity for 5-HT 1A R over both the α 1 and D 2 receptors. These results confirmed the hypothesis suggested in the literature that the terminal amide function of LCAPs is not critical for binding. , On the basis of the above results and with the aim to improve affinity and selectivity for 5-HT 1A R, in this work we describe the synthesis and the binding data for 5-HT 1A Rs, α 1 -ARs, 5-HT 2A serotonergic, D 1 , and D 2 dopaminergic receptors of a new class of arylpiperazinylthioalkyl derivatives ( 16 − 38 ) (Chart ).…”