Design, synthesis and melatoninergic activity of new unsubstituted and β,β′-difunctionalised 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-6-alkanamides

A series of new 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-6-alkanamides, with and without alkyl and cycloalkyl moieties in the β-position of the alkanamido side chain, have been prepared and tested for their ability to activate pigment granule aggregation in Xenopus laevis melanophores and bind to the recombinant human MT1 and MT2 melatonin receptor subtypes expressed in NIH 3T3 cells. An increase of the spacer's length in the side chain by a methylene unit (from 17d to 21d) leads to a six-fold decrease in antagonistic activity. On the other hand, the introduction of two methyl groups in the β-position of the side chain of 17a induces agonist potency (compound 24), implying thus that the two β-methyl groups are not only tolerated by the receptor, but constitute functional probes in its dynamic agonist–antagonist conformational equilibrium. The presence of more bulky β-substituents, regardless of the size of the R group, compounds 24a,b, seems to lead to antagonism and to a noteworthy MT2 subtype selectivity. Last, the new N1–C7 annulated derivatives presented herein are substantially more potent than their respective N1–C2 annulated counterparts, previously reported.

Graphical abstractA series of new unsubstituted and β,β′-difunctionalised 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-6-alkanamides have been prepared and tested for their melatoninergic potency. The nature of the response (agonist or antagonist activity) and the receptor subtype selectivity is dependent on both the side chain spacer's length and the size and shape of the β-substituents.Figure optionsDownload full-size imageDownload as PowerPoint slide