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Development of subnanomolar-affinity serotonin 5-HT4 receptor ligands based on quinoline structure

Abstract

Two small series of quinoline derivatives were designed starting from the previously published quinoline derivatives 7a,b in order to obtain information about their interaction with 5-HT4R binding site. Initially, the structure of 7a,b was modified by replacing their basic moiety with the one of partial agonist 4 (ML10302) or with that of reference ligand 6 (RS-67-333). Then, the aromatic moieties of 4-quinolinecarboxylates 7a,d-f,h-k or 4-quinolinecarboxamides 7b,c,g were modified into the ones of 2-quinolinecarboxamides 9a-e. Very interestingly, this structure-affinity relationship study led to the discovery of 7h-j as novel 5-HT4R ligands showing Ki values in the subnanomolar range. The structures of all these compounds contain the N-butyl-4-piperidinylmethyl substituent, which appeared to behave as an optimized basic moiety in the interaction of these 4-quinolinecarboxylates with 5-HT4R binding site. However, this basic moiety was ineffective in providing 5-HT4R affinity in the corresponding 4-quinolinecarboxamide 7g, but it did in 2-quinolinecarboxamide ligands 9c-e. Thus, a subtle interrelation of several structural parameters appeared to play a major role in the interaction of the ligands with 5-HT4R binding site. They include the kind of the basic moiety, the position of the carbonyl linking group with respect to the aromatic moiety and its orientation, which could be affected by the presence of the intramolecular H-bond as in compound 9c-e.

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Publication details

The article was received on 04 May 2018, accepted on 28 Jun 2018 and first published on 03 Jul 2018


Article type: Research Article
DOI: 10.1039/C8MD00233A
Citation: Med. Chem. Commun., 2018, Accepted Manuscript
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    Development of subnanomolar-affinity serotonin 5-HT4 receptor ligands based on quinoline structure

    F. Castriconi, M. Paolino, G. Grisci, C. M. Francini, A. Reale, G. Giuliani, M. Anzini, G. Giorgi, L. Mennuni, C. Sabatini, M. Lanza, G. Caselli and A. CAPPELLI, Med. Chem. Commun., 2018, Accepted Manuscript , DOI: 10.1039/C8MD00233A

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