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

J Martínez; S Pérez; A M Oficialdegui; B Heras; L Orús; H Villanueva; J A Palop; J Roca; M Mourelle; A Bosch; J C Del Castillo; B Lasheras; R Tordera; J del Río; A Monge

doi:10.1016/s0223-5234(00)01198-3

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

Eur J Med Chem. 2001 Jan;36(1):55-61. doi: 10.1016/s0223-5234(00)01198-3.

Authors

J Martínez¹, S Pérez, A M Oficialdegui, B Heras, L Orús, H Villanueva, J A Palop, J Roca, M Mourelle, A Bosch, J C Del Castillo, B Lasheras, R Tordera, J del Río, A Monge

Affiliation

¹ Department of Medicinal Chemistry and Centro de Investigación en Farmacobiología Aplicada (CIFA), Universidad de Navarra, C/ Irunlarrea s/n, 31080, Pamplona, Spain

PMID: 11231049
DOI: 10.1016/s0223-5234(00)01198-3

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antidepressive Agents / chemical synthesis
Antidepressive Agents / pharmacology*
Binding, Competitive / drug effects
Carrier Proteins / drug effects*
Carrier Proteins / metabolism
Dose-Response Relationship, Drug
GTP-Binding Proteins / metabolism
Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
Hippocampus / metabolism
In Vitro Techniques
Membrane Glycoproteins / drug effects*
Membrane Glycoproteins / metabolism
Membrane Transport Proteins*
Nerve Tissue Proteins*
Piperazines / chemical synthesis
Piperazines / metabolism
Piperazines / pharmacology*
Rats
Receptors, Serotonin / drug effects*
Receptors, Serotonin / metabolism
Receptors, Serotonin, 5-HT1
Selective Serotonin Reuptake Inhibitors / metabolism
Selective Serotonin Reuptake Inhibitors / pharmacology*
Serotonin Antagonists / metabolism
Serotonin Antagonists / pharmacology*
Serotonin Plasma Membrane Transport Proteins

Substances

Antidepressive Agents
Carrier Proteins
Membrane Glycoproteins
Membrane Transport Proteins
Nerve Tissue Proteins
Piperazines
Receptors, Serotonin
Receptors, Serotonin, 5-HT1
Serotonin Antagonists
Serotonin Plasma Membrane Transport Proteins
Serotonin Uptake Inhibitors
Slc6a4 protein, rat
Guanosine 5'-O-(3-Thiotriphosphate)
GTP-Binding Proteins