Improving the inhibitory activity of arylidenaminoguanidine compounds at the N-methyl-D-aspartate receptor complex from a recursive computational-experimental structure-activity relationship study.

Using a combination of both the partial least squares (PLS) and back-propagation artificial neural network (ANN) pattern recognition methods, several models have been developed to predict the activity of a series of arylidenaminoguanidine analogs as inhibitory modulators of the N-methyl-D-aspartate receptor complex. This was done by correlating structural and physicochemical descriptors obtained from computation software with the experimentally observed [(3)H]MK-801 displacement ability of a small library of synthesized and in vitro screened arylidenaminoguanidines. Results for the generated PLS model were r(2)=0.

Novel antiepileptic and anticonvulsive therapeutic agents.

Epilepsy is a broad-reaching central nervous system condition and the underlying pathology suggests a number of pharmacological pathways that can be targeted for drug therapy. These include ion channel modulation, historically the most investigated therapeutic approach, as well as regulation of excitatory and inhibitory neurotransmission. A broad range of drugs that act at each of these targets has been marketed, and promising new drug candidates are being developed constantly.

N-n-alkylpyridinium analogs, a novel class of nicotinic receptor antagonists: selective inhibition of nicotine-evoked [3H] dopamine overflow from superfused rat striatal slices.

Structural simplification of N-n-alkylnicotinium analogs, antagonists at neuronal nicotinic acetylcholine receptors (nAChRs), was achieved by removal of the N-methylpyrrolidino moiety affording N-n-alkylpyridinium analogs with carbon chain lengths of C1 to C20. N-n-Alkylpyridinium analog inhibition of [3H]nicotine and [3H]methyllycaconitine binding to rat brain membranes assessed interaction with alpha4beta2* and alpha7* nAChRs, respectively, whereas inhibition of nicotine-evoked 3H overflow from [3H]dopamine ([3H]DA)-preloaded rat striatal slices assessed antagonist action at nAChR subtypes mediating nicotine-evoked DA release. No inhibition of [3H]methyllycaconitine binding was observed, although N-n-alkylpyridinium analogs had low affinity for [3H]nicotine binding sites, i.