Hans Van de Waterbeemd

L‐Dopa esters as potential prodrugs: behavioural activity in experimental models of Parkinson's disease‡

Intraperitoneal administration of the 2‐tetrahydropyranylmethyl, phenoxyethyl, ethyl, 2‐hydroxypropyl and methyl ester prodrugs of L‐dopa produced locomotor activity in reserpine‐pretreated mice with equal intensity and duration to that observed following administration of L‐dopa itself. Administration of the 2‐(1‐methoxy)propyl ester produced a more prolonged effect while the p‐methoxyphenylethyl, n‐propyl, phenylethyl, m‐trifluoromethylbenzyl, cyclohexyl, p‐chlorophenylethyl and benzyl ester prodrugs were less active than L‐dopa itself. On oral administration, the ethyl and methyl ester prodrugs were more effective than L‐dopa in reversing reserpine‐induced akinesia in mice. The 2‐tetrahydropyranylmethyl, 2‐(1‐methoxy)propyl, 2‐hydroxypropyl, n‐propyl, benzyl and phenoxyethyl ester prodrugs produced effects comparable with those of L‐dopa. In contrast, the cyclohexyl, m‐trifluoromethylbenzyl, phenylethyl, p‐chlorophenylethyl and p‐methoxyphenylethyl ester prodrugs were less effective than L‐dopa on oral administration. Intraperitoneal administration of L‐dopa and the ester prodrugs of L‐dopa to rats with a prior 6‐hydroxydopamine (6‐OHDA) lesion of the medial forebrain bundle (MFB) produced contraversive circling responses. Rotation observed following administration of the n‐propyl, 2‐tetrahydropyranylmethyl, methyl and ethyl ester prodrugs was more intense than that observed following administration of L‐dopa itself. Rotation produced by the administration of L‐dopa and the cyclohexyl, 2‐(1‐methoxy)propyl, phenylethyl, p‐chlorophenylethyl, p‐methoxyphenylethyl, benzyl, 2‐hydroxypropyl, phenoxyethyl and m‐trifluoromethylbenzyl ester prodrugs was identical. Ester prodrugs of L‐dopa may be as effective as L‐dopa itself in producing motor activity but overall none of the compounds tested was markedly more potent or of longer duration than L‐dopa itself.

l-Dopa esters as potential prodrugs: effect on brain concentration of dopamine metabolites in reserpinized mice‡

The intraperitoneal administration of l‐Dopa and a series of ester prodrugs of l‐Dopa to reserpinized mice produced elevations of striatal and tuberculum olfactorium homovanillic acid (HVA) and 3,4‐dihydroxyphenylacetic acid (DOPAC) levels. Differences in the pattern of change produced by individual drugs, compared with l‐Dopa, were observed. Only the phenoxyethyl ester caused elevations of both striatal and tuberculum olfactorium HVA and DOPAC, greater than those measured following l‐Dopa administration. Overall the m‐trifluoromethylbenzyl, phenylethyl, p‐chlorophenylethyl and p‐methoxyphenylethyl ester prodrugs produced greater elevations of striatal and tuberculum olfactorium HVA, but not DOPAC, compared with l‐Dopa. The administration of the 2‐tetrahydropyranylmethyl derivative only enhanced striatal HVA and striatal and tuberculum olfactorium DOPAC concentrations. Changes of HVA and DOPAC tissue concentrations following administration of the 2‐hydroxypropyl, n‐propyl, methyl, ethyl and 2‐(1‐methoxy)propyl ester prodrugs were comparable with those produced by the administration of l‐Dopa itself. The alterations in striatal and tuberculum olfactorium HVA and DOPAC levels observed did not correlate with the ability of these compounds to elicit locomotor activity in reserpinized mice.

Influence of Lipophilicity and Chirality on the Selectivity of Ligands for β1‐ and β2‐Adrenoceptors

Abstract— Eudismic and QSAR analyses are reported for the β1‐ and β2‐adrenoceptor affinities and β1‐selectivity of 10 enantiomeric pairs of ligands with only N‐isopropyl or N‐t‐butyl groups. For both receptors, the eudismic index (ratio of affinity) increases with the affinity of the eutomers. However, the affinity of the distomers for the β2‐adrenoceptor is relatively high, suggesting additional hydrophobic interactions. This is confirmed by various correlations between affinities and lipophilicities, showing that the affinity for β2‐adrenoceptors is slightly more dependent on lipophilicity than that for β1‐adrenoceptors. As a result, the β1‐selectivity of the investigated β1‐adrenoceptor ligands is strongly and negatively correlated with their lipophilicity (r = −0.942).

Conformation, electrostatic potential and pharmacophoric pattern of orthopramides and other dopamine receptor antagonists

Abstract Theoretical and experimental conformational studies of orthopramides are reviewed and lead to the following conclusions for the compounds in solution. (i) For aminoethyl derivatives (e.g., metoclopramide) in the protonated form, folded and extended conformers of equal energy exist; the conformation of the non-protonated molecules is solvent-dependent. (ii) For 4-piperidyl derivatives (e.g., clebopride), only extended forms are possible under normal conditions. (iii) For 2-pyrrolidyl (e.g., sulpiride) and 3-pyrrolidyl derivatives (e.g., YM-08050), a relatively small energy difference exists between folded and extended forms. The extended form is thus postulated to be the one recognized by the receptor. Molecular electrostatic potential (MEP) calculations of the aromatic region of metoclopramide and halperidol show, in both cases, a positive and a negative edge. Superimposing the simplified and partial MEP of dopamine, metoclopramide and haloperidol leads to a pharmacophoric model of dopamine D-2 receptor ligands. These results are not compatible with a rigid and geometrical view of dopamine receptor topography.