title: New 1-aryl-3-(4-arylpiperazin-1-yl)propane derivatives, with dual action at 5-HT1A serotonin receptors and serotonin transporter, as a new class of antidepressants.
abstract: In a search toward new and efficient antidepressants, 1-aryl-3-(4-arylpiperazin-1-yl)propane derivatives were designed, synthesized, and evaluated for 5-HT reuptake inhibition and 5-HT1A receptor antagonism. This dual pharmacological profile should lead, in principle, to a rapid and pronounced enhancement in serotoninergic neurotransmission and consequently to a more efficacious treatment of depression. The design was based on coupling structural moieties related to inhibition of serotonin reuptake, such as gamma-phenoxypropylamines, to arylpiperazines, typical 5-HT1A ligands. In binding studies, several compounds showed affinity at the 5-HT transporter and 5-HT1A receptors. Antidepressant-like activity was initially assayed in the forced swimming test with those compounds with Ki < 200 nM in both binding studies. Functional characterization was performed by measuring the intrinsic effect on rectal temperature in mice and also the antagonism to 8-OH-DPAT-induced hypothermia. The most efficacious compounds (12f, 23gE, 28a, and 28b) were further explored for their ability to antagonize 8-OH-DPAT-induced inhibition of forskolin-stimulated cAMP formation in a cell line expressing the 5-HT1A receptor. Furthermore, the antidepressant-like properties of 12f, 28a, and 28b, which exhibited 5-HT1A receptor antagonistic property in the latter study, were also evaluated in the learned helplessness test in rats. Among these three compounds, 28b (1-benzo[b]thiophene-3-yl)-3-[4-(2-methoxyphenyl)-1-ylpropan-1-ol) showed the higher affinity at both the 5-HT transporter and 5-HT1A receptors (Ki = 20 nM in both cases) and was also active in the other pharmacological tests. Such a pharmacological profile could lead to a new class of antidepressants with a dual mechanism of action and a faster onset of action.
authors.affiliation: Department of Medicinal Chemistry, Centro de Investigación en Farmacobiología Aplicada, Universidad de Navarra, Pamplona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Martínez-Esparza
authors.forename: A M
authors.initials: AM
authors.lastname: Oficialdegui
authors.forename: S
authors.initials: S
authors.lastname: Pérez-Silanes
authors.forename: B
authors.initials: B
authors.lastname: Heras
authors.forename: L
authors.initials: L
authors.lastname: Orús
authors.forename: J A
authors.initials: JA
authors.lastname: Palop
authors.forename: B
authors.initials: B
authors.lastname: Lasheras
authors.forename: J
authors.initials: J
authors.lastname: Roca
authors.forename: M
authors.initials: M
authors.lastname: Mourelle
authors.forename: A
authors.initials: A
authors.lastname: Bosch
authors.forename: J C
authors.initials: JC
authors.lastname: Del Castillo
authors.forename: R
authors.initials: R
authors.lastname: Tordera
authors.forename: J
authors.initials: J
authors.lastname: Del Río
authors.forename: A
authors.initials: A
authors.lastname: Monge
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism*; D003114:Colony-Forming Units Assay; D003216:Conditioning, Operant / Q000187:drug effects; D000242:Cyclic AMP / Q000096:biosynthesis; D006367:HeLa Cells; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D009419:Nerve Tissue Proteins; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000928:Antidepressive Agents; D002352:Carrier Proteins; D000242:Cyclic AMP; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes; C431565:1-benzo(b)thiophen-3-yl)-3-(4-(2-methoxyphenyl)piperazin-1-ylpropan-1-ol; C493230:SLC6A4 protein, human; C493231:Slc6a4 protein, mouse