title: New arylpiperazines with flexible versus partly constrained linker as serotonin 5-HT(1A)/5-HT(7) receptor ligands.
abstract: 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 2H-1,3-benzoxazine-2,4(3H)-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.
authors.affiliation: Cracow University of Technology, Institute of Organic Chemistry and Technology, Kraków, Poland. kowapi@pk.edu.pl
authors.forename: Piotr
authors.initials: P
authors.lastname: Kowalski
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Mitka
authors.forename: Jolanta
authors.initials: J
authors.lastname: Jaśkowska
authors.forename: Beata
authors.initials: B
authors.lastname: Duszyńska
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
mesh_terms: D000818:Animals; D006801:Humans; D008024:Ligands; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D010879:Piperazines; D011985:Receptors, Serotonin; C104425:serotonin 7 receptor; D044282:Receptor, Serotonin, 5-HT1A