'Click' D1 receptor agonists with a 5-HT1A receptor pharmacophore producing D2 receptor activity

Abstract A series of new 1-aryl-3-benzazepine derivatives containing an arylpiperazinyl function as the N3 substituent were synthesized by combining a D 1 receptor agonistic pharmacophore and a 5-HT 1A receptor pharmacophore through Click reaction. Interestingly, these compounds generally do not have good binding affinity at the D 1 receptor, but most compounds are potent at both D 2 and 5-HT 1A receptors. Compound 8h , containing 1- m -tolyl-benzazepine scaffold and 2-methoxyphenylpiperazine core, displayed good affinity at all tested receptors, with K i values of 144, 80, and 133 nM, for the D 1 , D 2 , and 5-HT 1A receptors, respectively. Compound 13 with the triazole moiety formed differently from that in 8h showed the highest affinity at the D 2 receptor with K i value of 19 nM. This compound also showed moderate affinity at the 5-HT 1A ( K i , 105 nM), and D 1 ( K i , 551 nM) receptors. Functional assays indicated that both compounds 13 and 8h are antagonists at D 1 and D 2 receptors, whereas full agonistic activity at the 5-HT 1A receptor was observed. In agreement with the binding affinity, compound 13 is a high efficacy D 2 antagonist and 5-HT 1A agonist.