Design, synthesis and biological evaluation of new 3-[(4-aryl)piperazin-1-yl]-1-arylpropane derivatives as potential antidepressants with a dual mode of action: serotonin reuptake inhibition and 5-HT1A receptor antagonism.
It has been suggested that the combination of a selective serotonin reuptake inhibitor (SSRI) and a 5-HT1A receptor antagonist may facilitate the onset of the SSRIs antidepressant action. Accordingly, we describe the synthesis of a series of new 3-[(4-aryl)piperazin-1-yl]-1-arylpropane derivatives with structural modifications performed in Ar1, Ar2 and Z (Z is different functional groups) to obtain the sought dual activity. Compounds were evaluated for in vitro affinity at 5-HT1A receptors and 5-HT transporter. The antidepressant-like activity of derivatives with the higher affinity was assessed initially using the forced swimming test (FST). Compound 1-(2,4-dimethylphenyl)-3-[(2-methoxyphenyl)piperazin-1-il]-1-propa none (III.1.a) showed the best antidepressant-like activity which was further confirmed in the learned helplessness test.
Oficialdegui
A M
AM
Department of Medicinal Chemistry, Universidad de Navarra, Pamplona, Spain.
Martinez
J
J
Pérez
S
S
Heras
B
B
Irurzun
M
M
Palop
J A
JA
Tordera
R
R
Lasheras
B
B
del Río
J
J
Monge
A
A
D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005069:Evaluation Studies as Topic; D008297:Male; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000928:Antidepressive Agents; D010879:Piperazines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017367:Selective Serotonin Reuptake Inhibitors