New 3-[4-(aryl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propane derivatives with dual action at 5-HT1A serotonin receptors and serotonin transporter as a new class of antidepressants.
A series of new 3-[4-(aryl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propane derivatives were synthesized in an attempt to find a new class of antidepressant drugs with dual activity at 5-HT1A serotonin receptors and serotonin transporter. Title compounds were evaluated for in vitro activity on 5-HT1A receptor and 5-HT transporter. They show high nanomolar affinity for both activities, and in particular, compounds 1-(5-chlorobenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-1-ol (7) and 1-(5-fluorobenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-1-ol (8) show values (nM) of K(i)=30 and 2.3 for 5-HT1A receptors and K(i)=30 and 12 for serotonin transporters, respectively. In GTPgammaS binding assays, compound 8 revealed antagonist properties to 5-HT1A receptors. Such a pharmacological profile could lead to potent antidepressant agents with new dual mechanism of action.
Martínez
J
J
Department of Medicinal Chemistry and Centro de Investigación en Farmacobiología Aplicada (CIFA), Universidad de Navarra, C/ Irunlarrea s/n, 31080, Pamplona, Spain
Pérez
S
S
Oficialdegui
A M
AM
Heras
B
B
Orús
L
L
Villanueva
H
H
Palop
J A
JA
Roca
J
J
Mourelle
M
M
Bosch
A
A
Del Castillo
J C
JC
Lasheras
B
B
Tordera
R
R
del Río
J
J
Monge
A
A
D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins / Q000187:drug effects* / Q000378:metabolism; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology*; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism / Q000494:pharmacology*
D000928:Antidepressive Agents; D002352:Carrier Proteins; D019204:GTP-Binding Proteins; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493232:Slc6a4 protein, rat