Teunis Schuurman

Brain serotonin receptors as a target for the putative anxiolytic TVX Q 7821

In animal behavioral tests of anxiolytic efficacy, TVX Q 7821 was active and equipotent with diazepam, but did not produce muscle relaxation or anti-convulsant effects. The high affinity, specific binding of 3H-TVX Q 7821 to calf hippocampal membranes was displaced by serotonin (5-HT) but not by diazepam. Similarly, unlabeled TVX Q 7821 displaced 3H-5-HT but not 3H-flunitrazepam binding. Since ketanserin (a putative 5-HT2 ligand) was equally weak in displacing labeled 5-HT or TVX Q 7821, TVX Q 7821 may preferentially bind to 5-HT1, receptors.

Receptor interaction profile and CNS general pharmacology of metrifonate and its transformation product dichlorvos in rodents

In this study we assessed the possible effects of the putative Alzheimer therapeutic, metrifonate (39, 120, 390 μmol/kg), and its active transformation product, dichlorvos (4.5, 13.6, 45 μmol/kg), on the mammalian central nervous system (CNS). We did this by (1) investigating the receptor interaction profile of the two compounds in a range of in‐vitro radioligand binding assays, and (2) by studying the acute compound effects in rats and mice using a battery of behavioral tests after a single oral administration. Metrifonate and dichlorvos failed to displace various radioligands from their respective receptor binding sites on cell membranes at a concentration of 10 μM. In particular, there was no high‐affinity interaction with muscarinic or nicotinic acetylcholine receptor binding in‐vitro. In the modified Irwin test (rat) both compounds induced transient cholinergic symptoms after oral administration of a single dose of 390 μmol/kg metrifonate and 13.6–45 μmol/kg dichlorvos. The observed symptoms, such as salivation, tremor, and diarrhea, lasted for up to 75 min. In the open field test (rat) metrifonate increased the number of rearings at all doses, whereas dichlorvos had no effect on the parameters tested. Both compounds dose‐dependently reduced the pentylenetetrazole threshold dose in mice. In this test, only the highest dose of metrifonate, but all doses of dichlorvos, caused a significant reduction of the convulsion threshold dose. Metrifonate and dichlorvos did not influence traction ability in mice. Metrifonate and dichlorvos did not influence hexobarbital‐induced anesthesia in mice. Metrifonate induced hypothermia in rats only at the dose of 390 μmol/kg. Dichlorvos did not affect body temperature. No analgesic potential was observed in the hot‐plate test in mice. Furthermore, metrifonate and dichlorvos neither influenced motor coordination nor exhibited any cataleptic potential when administered to rats. Taken together, at cognition‐enhancing doses, metrifonate (39–120 μmol/kg) is safe and well tolerated. The adverse symptoms observed at higher doses, together with the apparent lack of high‐affinity interaction with neurotransmitter receptors in brain tissue and the similar profile of the active transformation product, dichlorvos, support the assumption that these compounds mediate a highly selective activation of the cholinergic system.

Nimodipin: Ein neuer pharmakologischer Ansatz zur Therapie primär degenerativer und Multiinfarkt-Demenz (PDD; MID)

Eine Reihe von physiologischen Prozessen, wie neuronale Erregbarkeit, Muskelkontraktion, Neurotransmitterfreisetzung, axonaler Transport, Enzymaktivitat etc. hangen von der intrazellularen Kalziumhomoostase ab. Wird diese gestort, so kommt es zu einer Reihe von pathophysiologischen Veranderungen, die sogar den Zelltod verursachen konnen (Boobis et al. 1989; Orrenius et al. 1989). Aufgrund der grosen Bedeutung von Kalzium bei intrazellularen Regulationsprozessen verwundert es nicht, das Nervenzellen viele Mechanismen entwickelt haben, die die intrazellulare Kalziumkonzentration regulieren (Gibson u. Peterson 1987; Khachaturian 1989).