Synthesis and Assessment of Fused β-Carboline Derivatives as Kappa Opioid Receptor Agonists

The synthesis of 5-formyl-6-aryl-6H-indolo[3,2,1-de][1,5] naphthyridine-2-carboxylates by reaction between 1-formyl-9H-beta-carbolines and cinnamaldehydes in the presence of pyrrolidine in water with microwave irradiation is described. Pharmacophoric modification of the formyl group offered several new fused beta-carboline derivatives, which were investigated for their kappa-opioid receptor (KOR) agonistic activity. Two compounds 4 a and 4 c produced appreciable agonist activity on KOR with EC50 values of 46 +/- 19 and 134 +/- 9 nM, respectively. Moreover, compound-induced KOR signaling studies suggested both compounds to be extremely G-protein-biased agonists. The analgesic effect of 4 a was validated by the increase in tail flick latency in mice in a time-dependent manner, which was completely blocked by the KOR-selective antagonist norBNI. Moreover, unlike U50488, an unbiased full KOR agonist, 4 a did not induce sedation. The docking of 4 a with the human KOR was studied to rationalize the result.

Automated summary

The synthesis of new fused beta-carboline derivatives led to the discovery of two compounds with significant agonistic activity on KOR, which were found to be extremely G-protein-biased agonists. These compounds demonstrated analgesic effects in mice, without inducing sedation, and their interaction with the human KOR was studied for rationalization of the results.