Dopamine and Serotonin Receptors: Amino Acid Sequences, and Clinical Role in Neuroleptic Parkinsonism.

DOI Web Site Web Site PubMed 被引用文献1件 参考文献250件
  • Seeman Philip
    Department of Pharmacology, Medical Science Building, Room 4344, University of Toronto
  • Corbett Roy
    Department of Biological Research, Neuroscience SBU, Hoechst-Roussel Pharmaceuticals Inc.
  • Nam Diane
    Department of Pharmacology, Medical Science Building, Room 4344, University of Toronto
  • Tol Hubert H.M. Van
    Department of Pharmacology, Medical Science Building, Room 4344, University of Toronto Molecular Neurobiology Laboratory, Clarke Institute of Psychiatry

この論文をさがす

抄録

This review summarizes the amino acid sequences of the human dopamine and serotonin receptors and their human variants. The review also examines the receptor basis of the atypical antipsychotic drugs that elicit less parkinsonism than the typical antipsychotics. Because the dissociation constant of a drug varies with the radioligand, the dissociation constants of many neuroleptics are here summarized for the dopamine D2-, D4- and serotonin S2A-receptors using different radioligands. Radioligands of low solubility in the membrane (having low tissue/buffer partition) result in lower values for the neuroleptic dissociation constants, compared to radioligands of high membrane solubility. Such studies yield the intrinsic K value for a neuroleptic in the absence of a competing ligand. Clozapine, for example, has an intrinsic K value of 1.6 nM at the D4-receptor, in agreement with the value of 1.6 nM when directly measured with [3H]clozapine at D4. However, because clozapine competes with endogenous dopamine, the in vivo clozapine concentration to occupy 75% of the dopamine D4-receptors is derived to be ?? 13 nM. This agrees with the value of 12 to 20 nM in the plasma water (or spinal fluid) observed in treated patients. Moreover, in L-DOPA psychosis (in Parkinson''s disease), the clozapine concentration for 75% blockade of D4 is predicted to be ?? 3 nM. This agrees with the value of ?? 1.2 nM observed by Meltzer et al. in plasma water (Neuropsychopharmacology, 12, 39-45 (1995)). This analysis supports the concept and practical value of the intrinsic K values. Some atypical neuroleptics (remoxipride, clozapine, perlapine, seroquel and melperone) have high intrinsic K values (ranging from 30 to 88 nM) at the D2-receptor, making them displaceable by high levels of endogenous dopamine in the caudate/putamen. In contrast, however, typical neuroleptics (i.e., those that typically cause parkinsonism) have intrinsic K values of 0.3 to 6 nM, making them less displaceable by endogenous dopamine. A relationship exists between the neuroleptic doses for rat catalepsy and the D2/D4 ratio of the intrinsic K values. Thus, the atypical neuroleptics appear to fall into two groups, those that bind loosely to D2 and those that are selective at D4.

収録刊行物

  • Jpn.J.Pharmacol.

    Jpn.J.Pharmacol. 71 (3), 187-204, 1996

    公益社団法人 日本薬理学会

被引用文献 (1)*注記

もっと見る

参考文献 (250)*注記

もっと見る

キーワード

詳細情報 詳細情報について

問題の指摘

ページトップへ