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.

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Biswas S, Hazeldine S, Ghosh B, Parrington I, Kuzhikandathil E, Reith ME, Dutta AK

J Med Chem. 2008 May 22;51(10):3005-19. doi: 10.1021/jm701524h. Epub 2008 Apr 12.

PubMed ID

18410082 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Dopamine	Dopamine D2 receptor	EC 50 (nM)	209	N/A	N/A	Details
Dopamine	Dopamine D3 receptor	EC 50 (nM)	8.53	N/A	N/A	Details