title: Synthesis and molecular modeling of new 1-aryl-3-[4-arylpiperazin-1-yl]-1-propane derivatives with high affinity at the serotonin transporter and at 5-HT(1A) receptors.
abstract: It has been proposed that 5-HT(1A) receptor antagonists augment the antidepressant efficacy of selective serotonin (5-HT) reuptake inhibitors. In a search toward new and efficient antidepressants, 1-(aryl)-3-[4-arylpiperazin-1-yl]-1-propane molecular hybrids were designed, synthesized, and evaluated for 5-HT reuptake inhibition and 5-HT(1A) receptor affinity. The design was based in coupling structural moieties related to inhibition of serotonin reuptake, such as benzo[b]thiophene derivatives to arylpiperazines, typical 5-HT(1A) receptor ligands. In binding studies, several compounds showed affinity at the 5-HT transporter and at 5-HT(1A) receptors. Molecular modeling studies predicted the pharmacophore elements required for high affinity binding and the features that enable to discriminate between agonist, partial agonist, or antagonist action at 5-HT(1A) receptors and 5-HT transporter inhibition. Solvent interactions in desolvation prior to the binding step along with enthalpy and enthropy compensations might be responsible to explain agonist, partial agonist, and antagonist character. Hydrogen-bonding capability seems to be important to break hydrogen interhelical hydrogen bonds or alternatively to form other bonds upon ligand binding. Partial agonists and antagonists are unable to do this as the full agonist, which interacts closely by long-range forces or directly. The compounds showing the higher affinity at both the 5-HT transporter (K(i) < 50 nM) and the 5-HT(1A) receptors (K(i) < 20 nM) were further explored for their ability to stimulate [(35)S]GTPgammaS binding or to antagonize 8-hydroxy-2-di-n-propylamino-tetralin (8-OH-DPAT)-stimulated [(35)]GTPgammaS binding to rat hippocampal membranes, an index of agonist/antagonist action at 5-HT(1A) receptors, respectively. Compound 8g exhibited agonist activity (EC(50) = 30 nM) in this assay, whereas compounds 7g and 8h,i behaved as weak partial agonists and 7h-j and 8j,l antagonized the R(+)-8-OH-DPAT-stimulated GTPgammaS binding. Functional characterization was performed by measuring the antagonism to 8-OH-DPAT-induced hypothermia in mice.
authors.affiliation: Department of Medicinal Chemistry, Centro de Investigación en Farmacobiología Aplicada (CIFA), Universidad de Navarra, C/ Irunlarrea s/n, 31080 Pamplona, Spain.
authors.forename: Lara
authors.initials: L
authors.lastname: Orús
authors.forename: Silvia
authors.initials: S
authors.lastname: Pérez-Silanes
authors.forename: Ana-M
authors.initials: AM
authors.lastname: Oficialdegui
authors.forename: Javier
authors.initials: J
authors.lastname: Martínez-Esparza
authors.forename: Juan-C
authors.initials: JC
authors.lastname: Del Castillo
authors.forename: Marisa
authors.initials: M
authors.lastname: Mourelle
authors.forename: Thierry
authors.initials: T
authors.lastname: Langer
authors.forename: Salvatore
authors.initials: S
authors.lastname: Guccione
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Donzella
authors.forename: Eva M
authors.initials: EM
authors.lastname: Krovat
authors.forename: Konstantin
authors.initials: K
authors.lastname: Poptodorov
authors.forename: Berta
authors.initials: B
authors.lastname: Lasheras
authors.forename: Santiago
authors.initials: S
authors.lastname: Ballaz
authors.forename: Isabel
authors.initials: I
authors.lastname: Hervías
authors.forename: Rosa
authors.initials: R
authors.lastname: Tordera
authors.forename: Joaquín
authors.initials: J
authors.lastname: Del Río
authors.forename: Antonio
authors.initials: A
authors.lastname: Monge
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007035:Hypothermia / Q000139:chemically induced; D066298:In Vitro Techniques; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D026901:Membrane Transport Proteins; D051379:Mice; D008958:Models, Molecular; D009419:Nerve Tissue Proteins; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011407:Propane / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011985:Receptors, Serotonin / Q000737:chemistry / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; D011407:Propane; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C493231:Slc6a4 protein, mouse; C493232:Slc6a4 protein, rat