title: Bioisosteric heterocyclic versions of 7-{[2-(4-phenyl-piperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-ol: identification of highly potent and selective agonists for dopamine D3 receptor with potent in vivo activity.
abstract: In the current report, we extend the SAR study on our hybrid structure 7-{[2-(4-phenyl-piperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-ol further to include heterocyclic bioisosteric analogues. Binding assays were carried out with HEK-293 cells expressing either D2 or D3 receptors with tritiated spiperone to evaluate inhibition constants (Ki). Functional activity of selected compounds in stimulating GTPgammaS binding was assessed with CHO cells expressing human D2 receptors and AtT-20 cells expressing human D3 receptors. The highest binding affinity and selectivity for D3 receptors were exhibited by (-)-34 (Ki=0.92 nM and D2/D3=253). In the functional GTPgammaS binding assay, (-)-34 exhibited full agonist activity with picomolar affinity for D3 receptor with high selectivity (EC50=0.08 nM and D2/D3=248). In the in vivo rotational study, (-)-34 exhibited potent rotational activity in 6-OH-DA unilaterally lesioned rats with long duration of action, which indicates its potential application in neuroprotective treatment of Parkinson's disease.
authors.affiliation: Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48202, USA.
authors.forename: Swati
authors.initials: S
authors.lastname: Biswas
authors.forename: Stuart
authors.initials: S
authors.lastname: Hazeldine
authors.forename: Balaram
authors.initials: B
authors.lastname: Ghosh
authors.forename: Ingrid
authors.initials: I
authors.lastname: Parrington
authors.forename: Eldo
authors.initials: E
authors.lastname: Kuzhikandathil
authors.forename: Maarten E A
authors.initials: ME
authors.lastname: Reith
authors.forename: Aloke K
authors.initials: AK
authors.lastname: Dutta
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016627:Oxidopamine / Q000633:toxicity; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D050637:Receptors, Dopamine D3 / Q000819:agonists*; D013237:Stereoisomerism; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000737:chemistry*
chemical_list: D000978:Antiparkinson Agents; D052160:Benzothiazoles; C529806:N(6)-(2-(4-(biphenyl-4-yl)piperazin-1-yl)ethyl)-N(6)-propyl-4,5,6,7-tetrahydrobenzo(d)thiazole-2,6-diamine; D018696:Neuroprotective Agents; D010879:Piperazines; D050637:Receptors, Dopamine D3; D013764:Tetrahydronaphthalenes; D016627:Oxidopamine