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J Pharmacol Exp Ther. 1994 Jan;268(1):417-26.

Expression and pharmacological characterization of the human D3 dopamine receptor.

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Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Essex, Great Britain.


Binding of dopamine receptor ligands to human D2 and D3 receptors was characterized in Chinese hamster ovary (CHO) cells using the dopamine D2 receptor antagonist [125I] iodosulpiride. Only limited binding selectivity was observed for known dopamine D2 receptor antagonists from a variety of chemical classes, which included haloperidol, chlorpromazine, sulpiride, pimozide and cis flupenthixol. The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. There was no evidence of functional coupling of the hD3 receptor to adenylate cyclase, arachidonic acid release, phospholipase C activation, K+ currents or calcium mobilization in any of the cell lines examined. Furthermore, guanine nucleotides failed to inhibit the binding of [3H] N-0437 to hD3 receptors in any of the three cell lines. There may be a number of explanations for these results. These cell lines may not have the appropriate G-protein or secondary messenger systems that are coupled to the hD3 receptor in situ. Alternatively, this receptor may couple by a mechanism that is as yet undefined. The finding that a wide range of structurally diverse human dopamine D2 (hD2) receptor agonists have an apparent hD3 selectivity may imply that the hD3 receptor exists predominantly in a high affinity state.

[Indexed for MEDLINE]

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