1,2,3,4-tetrahydroisoqunolines are of great importance to many different biological targets [1] and are frequently used as tool compounds to investigate the ligand–serotonergic receptor interactions [2,3]. The screening of our library of tetrahydroisoquinoline derivatives for 5-HT₇ receptor affinity led to the identification of MM 199 (tetrahydroisoquinoline analog of buspirone) and AK 30 (tetrahydroisoquinoline analog of NAN-190) having good 5-HT₇ receptor affinity.

To continue our studies on development of potent and selective 5-HT₇ receptor ligands we designed and synthesized a series of MM 199 and AK 30 analogs with modified tetrahydroisoquinoline fragment. We studied the effect of the introduction of methyl and benzyl substituent into the 2 position of amine moiety or spacer elongation on 5-HT₇ receptor affinity. Moreover, the structural variations included also changes of terminal imide fragments. The affinity for serotonergic receptor subtypes 5-HT₇ and 5-HT_1A were determined and some structure–affinity relationships are discussed.

This study was partly supported by the Ministry of Science and Higher Education (MNiSW), Grant No. 2 P05F 019 30.

[1] Vetulani, J.; Pavone, F.; Przewłocka, B.; Borghi, V.; Nalepa, I. J. Neural. Transm. 2003, 1205-1213.
[2] Bojarski, A.J.; Mokrosz, J.M.; Charakchieva Minol, S.; Kozioł, A.; Wesołowska, A.; Tatarczyńska, E.; Kłodzińska, A.; Chojnacka-Wójcik, E. Bioorg. Med. Chem. 2002, 10, 87-95.
[3] Leopoldo, M. Curr. Med. Chem. 2004, 11, 629-661.

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