No abstract

This paper correlates the X-ray structures of two 4-(beta-1-naphthylvinyl)pyridine analogues (one cis and one trans) with chemical and biological activity data for this class of cholineacetylase inhibitors. Our results suggest that one of the two proposed mechanisms for inhibition by this class of compounds better describes their efficacy. Previous arguments about coplanarity of the aromatic rings and nucleophilicty across the vinyl linkage need to be modified. Quantum calculations are also included and substantiate previous suggestions about the charge distribution across the vinyl linkages. An alternate new mechanism of inhibition is proposed to encompass the published data and more recent results discussed in this paper.

The effect of various concentrations of pentylenetetrazol (PTZ) on [3H]flunitrazepam binding to benzodiazepine receptors was investigated by Hofstee and Hill plot analyses. These analyses indicate the presence of two PTZ binding sites in forebrain, whereas a single PTZ binding site is present in cerebellum. The relative proportions of the two PTZ binding sites in forebrain are close to those of benzodiazepine Type II and Type I receptors, respectively. These results suggest that PTZ may actually discriminate between different types of benzodiazepine receptors.

No abstract

The potencies of seven benzodiazepines (BDZs) were established by three tests: inhibition of [3H]flunitrazepam receptor binding, inhibition of [3H]adenosine uptake, and prevention of pentylenetetrazol-induced seizures in mice. There is a high correlation between the potency for inhibition of [3H]flunitrazepam receptor binding and the antipentylenetetrazol potencies of benzodiazepines (r = 0.941; p less than 0.01). The antipentylenetetrazol potencies of benzodiazepines correlate well with their ability to inhibit [3H]adenosine uptake (r = 0.860; p less than 0.05 and greater than 0.01). However, there is no significant correlation between the potency for the inhibition of [3H]flunitrazepam receptor binding and the potency for inhibition of [3H]adenosine uptake (r = 0.751; p greater than 0.05). In addition, there is a marked difference in BDZ potency as measured by these two tests in vitro. The ratios of the Ki values (Ki2/Ki1) range from 98 for BDZ I to 64615 for clonazepam. The data presented indicate that antipentylenetetrazol activity of benzodiazepines results from an interaction between BDZ and nanomolar affinity BDZ receptors.