‘Click’ D1 receptor agonists with a 5-HT1A receptor pharmacophore producing D2 receptor activity Original Research Article

A series of new 1-aryl-3-benzazepine derivatives containing an arylpiperazinyl function as the N3 substituent were synthesized by combining a D1 receptor agonistic pharmacophore and a 5-HT1A receptor pharmacophore through Click reaction. Interestingly, these compounds generally do not have good binding affinity at the D1 receptor, but most compounds are potent at both D2 and 5-HT1A receptors. Compound 8h, containing 1-m-tolyl-benzazepine scaffold and 2-methoxyphenylpiperazine core, displayed good affinity at all tested receptors, with Ki values of 144, 80, and 133 nM, for the D1, D2, and 5-HT1A receptors, respectively. Compound 13 with the triazole moiety formed differently from that in 8h showed the highest affinity at the D2 receptor with Ki value of 19 nM. This compound also showed moderate affinity at the 5-HT1A (Ki, 105 nM), and D1 (Ki, 551 nM) receptors. Functional assays indicated that both compounds 13 and 8h are antagonists at D1 and D2 receptors, whereas full agonistic activity at the 5-HT1A receptor was observed. In agreement with the binding affinity, compound 13 is a high efficacy D2 antagonist and 5-HT1A agonist.