Cholinergic agents: effect of methyl substitution in a series of arecoline derivatives on binding to muscarinic acetylcholine receptors.

Arecoline, arecaidine, and a series of derivatives, differing by the presence or absence of methyl groups at positions on the periphery of the molecule, were prepared, and their binding to muscarinic acetylcholine receptors was tested. On the basis of this study, muscarinic agonism for arecoline series is governed by strict structure-activity relationships, as previously observed for other agonist series. Only minor changes in nitrogen substitution were tolerated in the present series of arecoline derivatives.

N-phenyl-N'-pyridinylureas as anticonvulsant agents.

A series of N-phenyl-N'-pyridinylureas was examined for anticonvulsant activity. Extensive structure/activity investigations revealed optimal activity in the N-(2,6-disubstituted-phenyl)-N'-(4-pyridinyl)urea series, with 37 exhibiting the best overall anticonvulsant profile. Compound 37 was effective against seizures induced by maximal electroshock but did not protect mice from clonic seizures produced by the convulsant pentylenetetrazol.

3-Phenoxypyridine 1-oxides as anticonvulsant agents.

The anticonvulsant activity of a series of 3-phenoxypyridine 1-oxides is described. An investigation carried out to optimize the activity/side effect ratio provided 4-methyl-3-phenoxypyridine 1-oxide, 3, as the derivative of choice. Overall, 3 has a pharmacological profile that is very similar to phenytoin.

Synthesis and potential antipsychotic activity of 1H-imidazo[1,2-c]pyrazolo[3,4-e]pyrimidines.

The synthesis of a series of 1H-imidazo[1,2-c]pyrazolo[3,4-e]pyrimidines is reported along with the effects of these compounds in preclinical tests for antipsychotic activity. Certain of these compounds displayed antipsychotic-like effects in conditioned avoidance tests, but unlike currently used antipsychotic drugs, they did not have affinity for brain dopamine receptors. These compounds also did not cause dystonias predictive of extrapyramidal side effects in monkeys at doses that produced behavioral effects.

6-Alkoxy-N,N-disubstituted-2-pyridinamines as anticonvulsant agents.

The anticonvulsant effect of a series of 6-alkoxy-N,N-disubstituted-2-pyridinamines is described. An investigation was carried out to optimize the activity/side-effect ratio in this series of compounds. The most desirable profile was seen with 1-[6-(2-methylpropoxy)-2-pyridinyl]piperazine, 6, and this compound was selected for a more complete pharmacological evaluation.