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New Arylpiperazines with Flexible versus Partly Constrained Linker as Serotonin 5‐HT 1A /5‐HT 7 Receptor Ligands
Author(s) -
Kowalski Piotr,
Mitka Katarzyna,
Jaśkowska Jolanta,
Duszyńska Beata,
Bojarski Andrzej J.
Publication year - 2013
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201300011
Subject(s) - chemistry , piperazine , pharmacophore , moiety , stereochemistry , linker , tetrahydroisoquinoline , 5 ht receptor , amine gas treating , receptor , serotonin , combinatorial chemistry , organic chemistry , biochemistry , computer science , operating system
A series of new long‐chain arylpiperazine (LCAP) derivatives with flexible and partly constrained alkyl linker were synthesized and investigated in vitro as potential serotonin 5‐HT 1A and 5‐HT 7 receptor ligands. The compounds were prepared by a two‐step procedure using naphthalimide and 2 H‐ 1,3‐benzoxazine‐2,4(3 H )‐dione as imides, and 1‐(2‐methoxyphenyl)piperazine ( o ‐OMe‐PhP) and 1,2,3,4‐tetrahydroisoquinoline (THIQ) as amine pharmacophores. Modifications of the spacer structure included introduction of flexible penta‐ and hexamethylene chains as well as partly constrained m ‐ and p ‐xylyl moieties. In general, the new compounds were more active at the 5‐HT 1A than at the 5‐HT 7 receptor, and the o ‐OMe‐PhP derivatives displayed higher affinities than their respective THIQ analogs. The spacer modifications had little effect on the observed in vitro activities. Within the o ‐OMe‐PhP series, except for a small binding reduction for ligands containing the m ‐xylyl moiety, there was no substantial change in the compounds' potency at both receptors, while for the THIQ derivatives a clear structure–activity relationship was visible only for the interaction of the compounds with the 5‐HT 7 receptor, which strongly favored flexible analogs.