Scandinavian Review

Seeman, Kenneth

doi:10.1176/appi.psychotherapy.1978.32.2.323

Cited by 8 publications

(18 citation statements)

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“…The D2 dopamine receptor is of particular interest owing to its association with certain clinical conditions, e.g. schizophrenia, Parkinson's disease or their drug treatments (Iversen, 1976;Seeman, 1980) and several groups have solubilized this receptor and achieved partial purification (for review, see Strange, 1987). Here we describe our studies on the purification and molecular characterization of this important receptor and site of drug action.…”

Section: Introductionmentioning

confidence: 99%

Purification of brain D2 dopamine receptor.

et al. 1988

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D2 dopamine receptors have been extracted from bovine brain using the detergent cholate and purified approximately 20,000‐fold by affinity chromatography on haloperidol‐sepharose and wheat germ agglutinin‐agarose columns. The purified preparation contains D2 dopamine receptors as judged by the pharmacological specificity of [3H]spiperone binding to the purified material. The sp. act. of [3H]spiperone binding in the purified preparation is 2.5 nmol/mg protein. The purified preparation shows a major diffuse band at Mr 95,000 upon SDS‐polyacrylamide gel electrophoresis and there is evidence for microheterogeneity either at the protein or glycosylation level. Photoaffinity labelling of D2 dopamine receptors also shows a species of Mr 95,000. The D2 dopamine receptor therefore is a glycoprotein of Mr 95,000.

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Section: Introductionmentioning

confidence: 99%

Purification of brain D2 dopamine receptor.

et al. 1988

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“…Activity at D-1 receptors appears dependent to some extent on lipid solubility but within a wide range of lipid solubilities steric factors also dictate the interaction of neuroleptic drugs with these receptor sites. This conclusion is strengthened by the fact that functional neuroleptic activity is associated with the activity of these drugs at D-2 sites (Seeman 1980;Leysen 1982). Indeed, in the present study, correlation matrix analysis showed a high degree of correlation between the ability of neuroleptic drugs to displace [3H]spiperone and their ability to inhibit apomorphine-induced stereotyped behaviour (Table 3).…”

Section: Discussionmentioning

confidence: 99%

Potent lipophilic substituted benzamide drugs are not selective D-1 dopamine receptor antagonists in the rat

Fleminger

Waterbeemd

Rupniak

et al. 1983

Journal of Pharmacy and Pharmacology

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The substituted benzamide drugs YM 09151-2 and clebopride potently inhibited apomorphine-induced stereotyped behaviour in the rat and caused displacement of the specific binding of [3H]spiperone to D-2 binding sites on striatal membranes in low nanomolar concentrations. Other substituted benzamide drugs including metoclopramide, sultopride and flubepride also inhibited stereotyped behaviour to a greater or lesser degree, but were less potent in displacing [3H]spiperone from D-2 sites. YM 09151-2 and clebopride only weakly displaced specific binding of [3H]piflutixol to D-1 sites on rat striatal membranes, and only weakly inhibited striatal dopamine stimulated adenylate cyclase activity, when compared with cis-flupenthixol. The other substituted benzamide drugs did not displace [3H]piflutixol or inhibit dopamine stimulation of adenylate cyclase activity in the concentration range used. Clebopride and YM 09151-2 were highly lipophilic with apparent partition coefficient (log P') values equivalent to those of classical neuroleptic compounds, such as cis-flupenthixol. In contrast, the other substituted benzamide drugs were markedly less lipophilic. A log P' value of approximately 2 was required before inhibition of adenylate cyclase activity or displacement of [3H]piflutixol binding occurred. However, in excess of this value there was no correlation between either inhibition of adenylate cyclase activity or displacement of [3H]piflutixol binding and the lipophilicity of the various compounds. We conclude that potent lipophilic substituted benzamide drugs, like other members of the substituted benzamide series, are selective D-2 receptor antagonists. Inherent steric factors within the drug series would appear to dictate activity at D-1 and D-2 sites, although lipophilicity may contribute to actions in these environments.

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“…It was shown that in equimolar doses the 5,6-derivatives produce higher brain concentrations than their 6,7-isomers and that this was largely due to a difference in their susceptibility to undergo O-methylation by catechol-O-methyl transferase (COMT) (Rollema et a1 1980). The ratio of in-vivo activities of the 5,6and the 6,7-isomers (measured as the potency to decrease the concentrations of the D A metabolites dihydroxy-phenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum) when corrected for the differences in brain concentrations, was for both the primary amines and the dipropylamino derivatives the same as that reported for their in-vitro dopaminergic activity (inhibition of [3H-]apomorphine and [3H]spiperone binding; activation of DA-sensitive adenylate cyclase (Seeman 1980;Cannon et a1 1978)). Here we report the extension of this approach to include apomorphine, which contains in its structure the 5,6rather than the 6,7-dihydroxy-aminotetralin nucleus.…”

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confidence: 80%

“…Among the large number of dopamine (DA) receptor agonists available, are compounds derived from apomorphine, 2-aminotetralin (2-aminotetrahydronaphthalene), DA itself and various ergoline and octahydrobenzoquinoline structures (Seeman 1980). Besides covering a wide range of activities, these compounds show large variations in physico-chemical properties and in their susceptibility to metabolic degradation.…”

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confidence: 99%