8-hydroxy-2-(di-n-propylamino)tetralin-hydrobromide and Hypothermia

A series of new derivatives of 4-aryl-pyrido[1,2-c]pyrimidine containing the 3-(4-piperidyl)-1H-indole residue or its 5-methoxy derivative were synthesized. They were characterized (i) in vitro by binding to 5-HT(1A) receptors and 5-HT transporter proteins in rat brain cortex membranes and (ii) in vivo in the mouse by induced hypothermia and forced swimming models for antagonist/agonist activity against the 5-HT(1A) autoreceptors and postsynaptic 5-HT(1A) receptors, respectively. Structure activity relationship evaluation indicated that the presence of the 3-(4-piperidyl)-1H-indole residue and ortho- or para-substituents with -F or -CH(3) groups in the aryl ring as well as an unsubstituted aryl in the 4-aryl-pyrido[1,2-c]pyrimidine moiety promoted low K(i) values for both receptors. In contrast, the presence of a 5-methoxy-3-(4-piperidyl)-1H-indole residue as well as -Cl or -OCH(3) substituents at the para position markedly reduced the receptor affinity.

Topics: Animals; Body Temperature; Drug Design; Hypothermia; Immobilization; Ligands; Male; Mice; Piperazine; Piperazines; Pyridines; Pyrimidines; Receptor, Serotonin, 5-HT1A; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT1 Receptor Agonists; Serotonin Plasma Membrane Transport Proteins; Swimming