6533b835fe1ef96bd129eb62

RESEARCH PRODUCT

Synthesis and pharmacology of 6-substituted benztropines: discovery of novel dopamine uptake inhibitors possessing low binding affinity to the dopamine transporter

Riccardo RondaninMarinella RobertiMarcello RossiSilvia MarinoValerio BertolasiStefania MerighiDaniele SimoniStefania GrimaudoDaniela PizziraniAnna SiniscalchiPier Andrea BoreaKatia VaraniManlio TolomeoStefania GessiFrancesco Paolo InvidiataRiccardo BaruchelloSabrina CavalliniClementina Bianchi

subject

StereochemistryDopamineDopamine Plasma Membrane Transport ProteinsMolecular ConformationNerve Tissue ProteinsIn Vitro TechniquesBinding CompetitiveDopamine Plasma Membrane Transport ProteinRadioligand AssayStructure-Activity Relationshipchemistry.chemical_compoundDopamine Uptake InhibitorsCocaineDopaminetriple reuptakeDrug DiscoveryDopamine Uptake InhibitorsmedicineAnimalsStructure–activity relationshipDopamine transporterBenztropineNerve EndingsDopamine Plasma Membrane Transport ProteinsMembrane GlycoproteinsbiologyPutamenMembrane Transport ProteinsStereoisomerismTropaneBiological activityCorpus StriatumBenztropineRatschemistrybiology.proteinMolecular MedicineTropanesmedicine.drug

description

A series of 6alpha- and 6beta-substituted benztropines were synthesized. A marked enantioselectivity was observed for the 6beta-methoxylated benztropines, the (1R)-isomers being more potent than the corresponding (1S) compounds. The racemic 6alpha-methoxy-3-(4',4' '-difluorodiphenylmethoxy)tropane (5 g) was the most potent compound. It has been found that modifications at the 6-position of benztropine might reduce the DAT binding affinity, maintaining otherwise a significant dopamine uptake inhibitory activity. A reinvestigation of the absolute configuration of 6beta-methoxytropinone proved the 6R configuration for the (+)-enantiomer.

yearjournalcountryeditionlanguage
2005-01-01
10.1021/jm0490235http://hdl.handle.net/10447/14975