LAUSR

The synthesis of 5‐formyl‐6‐aryl‐6H‐indolo[3,2,1‐de][1,5] naphthyridine‐2‐carboxylates by reaction between 1‐formyl‐9H‐β‐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 β‐carboline derivatives, which were investigated for their κ‐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.