Systematic in vivo screening of a series of 1-propyl-4-arylpiperidines against dopaminergic and serotonergic properties in rat brain: a scaffold-jumping approach.

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Mattsson C, Andreasson T, Waters N, Sonesson C

Systematic in vivo screening of a series of 1-propyl-4-arylpiperidines against dopaminergic and serotonergic properties in rat brain: a scaffold-jumping approach.

J Med Chem. 2012 Nov 26;55(22):9735-50. doi: 10.1021/jm300975f. Epub 2012 Oct 17.

PubMed ID

23043306 [ View in PubMed

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Abstract

A series of 1-propyl-4-arylpiperidines were synthesized and their effects on the dopaminergic and serotonergic systems tested in vivo and in vitro. Scaffold jumping among five- and six-membered bicyclic aryl rings attached to the piperidine ring had a marked impact on these effects. Potent and selective dopamine D(2) receptor antagonists were generated from 3-indoles, 3-benzoisoxazoles, 3-benzimidazol-2-one, and 3-benzothiophenes. In contrast, 3-benzofuran was a potent and selective inhibitor of monoamine oxidase (MAO) A. The effects of the synthesized compounds on 3,4-dihydroxyphenylacetic acid (DOPAC) levels correlated very well with their affinity for dopamine D(2) receptors and MAO A. In the 4-arylpiperidine series, the most promising compound for development was the 6-chloro-3-(1-propyl-4-piperidyl)-1H-benzimidazol-2-one (19), which displayed typical dopamine D(2) receptor antagonist properties in vivo but produced only a partial reduction on spontaneous locomotor activity. This indicates that the compound may have a lower propensity to induce parkinsonism in patients.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Pimozide	Dopamine D2 receptor	Ki (nM)	11.7	N/A	N/A	Details
Ziprasidone	Dopamine D2 receptor	Ki (nM)	8.5	N/A	N/A	Details