Synthesis, NMR conformational analysis and pharmacological evaluation of 7,7a,13,14-tetrahydro-6H-cyclobuta[b]pyrimido[1,2-a:3,4-a′]diindole analogues as melatonin receptor ligands

A structure for the self-condensation product of 2-(1H-indol-2-yl)ethyl tosylate2a, previously proposed as 6,7,14,15-tetrahydro-15aH-azocino[1,2-a:6,5-b]diindole3a, was revised based on the 13C-2D-INADEQUATE experiment, and proved to be 7,7a,13,14-tetrahydro-6H-cyclobuta[b]pyrimido[1,2-a:3,4-a′]diindole4a. A mechanism for the unexpected formation of this novel hexacyclic heterocycle was proposed and its NMR solution structure was elucidated. Five derivatives of the title ring skeleton 12–16 designed as melatonin receptor ligands were synthesized and their affinities for the human MT1 and MT2 receptors were determined. Both butyramides 13 and 15, as well as the non-methoxy acetamide 12 exhibited micromolar binding affinities for both receptors being slightly MT2 selective. The methoxy acetamide 14 showed the best pharmacological profile exhibiting a five times higher affinity for MT1 (Ki = 49 nM) than for MT2 (Ki = 246 nM) receptor.