Novel photoaffinity label for the dopamine D2 receptor: synthesis of 4-amino-5-iodo-2-methoxy-N-[1-(phenylmethyl)-4-piperidinyl]benzamide (iodoazidoclebopride, IAC) and the corresponding 125I-labeled analog (125IAC)

Journal of Medicinal Chemistry
1985.0

Abstract

Dopamine agonist elecited behaviors (rotation, psychotomimetic actions, antiparkinsonian action, stereotypy, and locomotion) appear to be mediated by dopamine D2 receptors in the brain. Although the dopamine D2 receptor has been solubilized by several laboratories, attempts to isolate and purify the protein by affinity chromatography or photoaffinity labeling have been relatively unsuccessful. Alkylating type irreversible ligands have been developed (i.e., [3H]-N-(chloroethyl)norapomorphine, phenoxybenzamine, N-(ethoxycarbonyl)-2-ethoxy-1,2-dihydroquinoline, flupenthixyl chloride), but have been too low in receptor affinity and/or selectivity to be of value in dopamine D2 receptor isolation. The molecular characterization of dopamine D2 receptors has been hampered by the lack of specific photoaffinity probes which can be used to covalently label these sites. We report here the synthesis of a series of substituted benzamides (Ib-Ig) and in particular Ig, an agent useful as a photoaffinity label, which selectively and irreversibly labels dopamine D2 receptors upon light irradiation.

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