Development of subnanomolar-affinity serotonin 5-HT receptor ligands based on quinoline structures.

Two small series of quinoline derivatives were designed starting from previously published quinoline derivatives and in order to obtain information about their interaction with the 5-HTR binding site. Initially, the structure of and was modified by replacing their basic moiety with that of partial agonist (ML10302) or with that of reference ligand (RS-67-333). Then, the aromatic moieties of 4-quinolinecarboxylates , , and or 4-quinolinecarboxamides , , and were modified into those of 2-quinolinecarboxamides . Very interestingly, this structure-affinity relationship study led to the discovery of as novel 5-HTR ligands showing values in the subnanomolar range. The structures of all these compounds contain the -butyl-4-piperidinylmethyl substituent, which appear to behave as an optimized basic moiety in the interaction of these 4-quinolinecarboxylates with the 5-HTR binding site. However, this basic moiety was ineffective in providing 5-HTR affinity in the corresponding 4-quinolinecarboxamide , but it did in 2-quinolinecarboxamide ligands . Thus, a subtle interrelationship of several structural parameters appeared to play a major role in the interaction of the ligands with the 5-HTR binding site. They include the kind of 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 compounds .