Dopamine D4-like binding sites labeled by [3H]nemonapride include substantial serotonin 5-HT2A receptors in primate cerebral cortex.
Dopamine D4-like binding sites are abundant in human cerebral cortex as detected by [3H]nemonapride. The extremely low density of D4 mRNA in human cerebral cortex is inconsistent with the high amount of D4-like binding sites. To investigate the nature of the D4-like receptors, [3H]nemonapride binding sites in the nonhuman primate cerebral cortex were characterized. Although [3H]nemonapride binding sites were D4-like, displaceable by clozapine but not raclopride, [3H]nemonapride binding was not displaced by selective D4 antagonists but was displaced by the selective 5-HT2A antagonist MDL100907. Using [3H]ketanserin as a 5-HT2A ligand, nemonapride showed high affinity for monkey (Ki = 10.4 nM) and cloned human (Ki = 9.4 nM) 5-HT2A receptors, while its affinity for rat receptors was lower (Ki = 140 nM). The present study demonstrates that cerebral cortical D4-like binding sites labeled by [3H]nemonapride in nonhuman primates consist of a very small portion of D4, but a substantial portion of 5-HT2A receptors. The unexpectedly high affinity of nemonapride for primate 5-HT2A receptor suggests reconsidering previous data from other studies using [3H]nemonapride, particularly those on D4-like receptors.
Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
K
K
Noda-Saita
M
M
Matsumoto
K
K
Hidaka
K
K
Hatanaka
J
J
Ohmori
M
M
Okada
T
T
Yamaguchi
D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D001549:Benzamides / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D006801:Humans; D007650:Ketanserin / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008252:Macaca fascicularis; D010869:Pindolol / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050638:Receptors, Dopamine D4; D011985:Receptors, Serotonin / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D014316:Tritium; D000096926:Benzenesulfonamides
D000840:Anisoles; D001549:Benzamides; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D007650:Ketanserin; D008024:Ligands; D010869:Pindolol; D010879:Piperazines; D011437:Propylamines; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; D011985:Receptors, Serotonin; D013449:Sulfonamides; D014316:Tritium; C104859:(R)-5-chloro-4-cyclopropylcarbonylamino-2-methoxy-N-(1-(3-methoxybenzyl)-3-pyrrolidinyl)benzamide monooxalate; C493599:DRD4 protein, human; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride; C100448:sonepiprazole; D000096926:Benzenesulfonamides; C030265:nemonapride