title: The influence of substitution at aromatic part of 1,2,3,4-tetrahydroisoquinoline on in vitro and in vivo 5-HT(1A)/5-HT(2A) receptor activities of its 1-adamantoyloaminoalkyl derivatives.
abstract: Further structure-activity relationship (SAR) studies with the 1,2,3,4-tetrahydroisoquinoline (THIQ) class of 5-HT(1A) ligands led to the synthesis of new 1-adamantoyloaminoalkyl derivatives. The impact of substituent variations in the aromatic part of THIQ moiety on 5-HT(1A) and 5-HT(2A) receptor affinities, as well as in vivo functional properties of the investigated compounds were discussed. It was found that those modifications reduced the binding affinity for 5-HT(1A) receptors (in comparison with unsubstituted THIQ derivatives); however, the majority of new compounds still remained potent 5-HT(1A) ligands (K(i)=4.9-46 nM) and most of them showed features of partial agonists of postsynaptic 5-HT(1A) receptors. At the same time, their 5-HT(2A) receptor affinity was slightly increased (K(i)=40-1475 nM), which resulted in a loss of 5-HT(2A)/5-HT(1A) selectivity. 5-Br,8-OCH3 derivative-the most potent, mixed 5-HT(1A)/5-HT(2A) ligand-produced activation of presynaptic 5-HT(1A) receptors and showed properties of a 5-HT(2A) receptor antagonist.
authors.affiliation: Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-143, Kraków, Poland. bojarski@if-pan.krakow.pl
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Mokrosz
authors.forename: Sijka Charakchieva
authors.initials: SC
authors.lastname: Minol
authors.forename: Aneta
authors.initials: A
authors.lastname: Kozioł
authors.forename: Anna
authors.initials: A
authors.lastname: Wesołowska
authors.forename: Ewa
authors.initials: E
authors.lastname: Tatarczyńska
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Kłodzińska
authors.forename: Ewa
authors.initials: E
authors.lastname: Chojnacka-Wójcik
mesh_terms: D000218:Adamantane / Q000737:chemistry*; D000818:Animals; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D012702:Serotonin Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines
chemical_list: D007546:Isoquinolines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D044005:Tetrahydroisoquinolines; C014843:1,2,3,4-tetrahydroisoquinoline; D000218:Adamantane