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.
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.
Bojarski
Andrzej J
AJ
Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-143, Kraków, Poland. bojarski@if-pan.krakow.pl
Mokrosz
Maria J
MJ
Minol
Sijka Charakchieva
SC
Kozioł
Aneta
A
Wesołowska
Anna
A
Tatarczyńska
Ewa
E
Kłodzińska
Aleksandra
A
Chojnacka-Wójcik
Ewa
E
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
D007546:Isoquinolines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D044005:Tetrahydroisoquinolines; C014843:1,2,3,4-tetrahydroisoquinoline; D000218:Adamantane