Biomedical subjects

H van de Waterbeemd

Publications and source records attributed to H van de Waterbeemd.

22 records · Page 2Linked to original sources

PubMed1984

L-Dopa methyl ester--a candidate for chronic systemic delivery of L-Dopa in Parkinson's disease.

Continuous intravenous infusions of L-Dopa as a treatment for response swings in Parkinson's disease are limited by the insolubility and acidity of L-Dopa. Its methyl ester is a soluble neutral derivative that might be of benefit to these patients, and is examined in the present study in behavioural and biochemical animal models. On intraperitoneal or subcutaneous administration to mice L-Dopa methyl ester was equivalent to L-Dopa in reversing reserpine-induced akinesia and producing contraversive circling behaviour in rats with a 6-hydroxydopamine lesion of the medial forebrain bundle. On oral administration the methyl ester was more active. The administration of L-Dopa or the methyl ester produced equivalent changes in striatal and mesolimbic dopamine, homovanillic acid, and 3,4-dihydroxyphenylacetic acid metabolite levels. We suggest that systemic or subcutaneous infusion of L-Dopa methyl ester to patients who experience response fluctuations may provide a means of maintaining mobility.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1983

Theoretical conformational studies on some dopamine antagonistic benzamide drugs: 3-pyrrolidyl- and 4-piperidyl derivatives.

Model derivatives of 3-pyrrolidyl- and 4-piperidyl-o-methoxybenzamides, as representatives of neuroleptic substituted benzamide drugs, have been investigated by theoretical conformational analysis. Folded conformers of 2-methoxy-N-(1-methyl-3-pyrrolidyl)benzamide have the lowest energy, but extended conformers are only a few kilocalories per mole less stable. As regards to piperidyl derivative, it has been found that folded conformers are of much higher energy than extended ones. These and previous results are discussed in terms of the pharmacologically active conformers of substituted benzamide drugs and of possible modes of interaction with the dopamine receptor.

Animals↗

PubMed1983

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

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.

Adenylyl Cyclases↗

PubMed1981

Transport in quantitative structure-activity relationships. VI: Relationship between transport rate constants and partition coefficients.

The transport rate constant of a drug partitioned in a two-phase system from an aqueous to an organic phase (k1obs) and vice versa (k2obs) is a function of the partition coefficient P and of a solvent system-dependent parameter beta. Drug transport is shown to be independent of molecular structure for a number of arbitrary compounds.

Biological Transport↗