Synthesis and Assessment of fused β-carboline derivatives as Kappa Opioid Receptor agonist.

Synthesis and Assessment of fused β-carboline derivatives as Kappa Opioid Receptor agonist.
ChemMedChem. 2021 Feb 17;:
Authors: Batra S, Yadav VD, Kumar L, Kumari P, Kumar S, Singh M, Siddiqi MI, Yadav PN
Abstract
The synthesis of 5-formyl-6-aryl-6H-indolo[3,2,1-de][1,5] naphthyridine-2-carboxylates via reaction between 1-formyl-9H-b-carbolines and cinnamaldehydes in the presence of pyrrolidine in water under microwave irradiation is described. Pharmacophoric modification of the formyl group offered several new fused-b-carboline derivatives which were investigated for their k-opioid receptor (KOR) agonistic activity. Two compounds 4a and 4c produced appreciable agonist activity on KOR with EC50 of 46±19 nM and 134±9 nM, respectively. Moreover, compound induced KOR signaling studies suggested both compounds to be extremely G-protein biased agonist. The analgesic effect of 4a was validated by the increase in tail flick latency in time dependent manner, which was completely blocked by KOR selective antagonist norBNI. Moreover, unlike U50488, an unbaised full KOR agonist, 4a did not induce sedation. The docking of 4a with the human KOR was studied to rationalize the result.
PMID: 33599108 [PubMed - as supplied by publisher]

Source: ChemMedChem - February 17, 2021 Category: Chemistry Authors: Batra S, Yadav VD, Kumar L, Kumari P, Kumar S, Singh M, Siddiqi MI, Yadav PN Tags: ChemMedChem Source Type: research