SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF PHENYLACETAMIDES AS SODIUM-CHANNEL BLOCKERS

The synthesis and structure-activity relationships of a series of phen ylacetamides related to 1-piperidinyl)propyl]-alpha-phenylbenzeneaceta mide (1) (PD85639) acting at the voltage-dependent Na+ channel are des cribed. All structural variations for this study were made in the phen ylacetic acid portion of these molecules, and the compounds were synth esized by coupling the appropriately substituted phenylacetic acid der ivative with 3-[1-(2,6-dimethyl)piperidinyl]propanamine using standard methods of amide formation. Compounds were tested as inhibitors of [H -3]batrachtoxinin binding in rat neocortical membranes and also as inh ibitors of veratridine-induced Naf influx in Chinese hamster ovary cel ls expressing type IIA Na+ channels. Diphenylacetic acid derivatives w ith halogenated aromatic rings (12-15) were very potent in both assays , while alkoxy and alkyl substitution did not affect activity (16 and 17). Selected compounds were tested as potential neuroprotective agent s in two cell culture assays involving inhibition of veratridine-induc ed and hypoxia-induced lactate dehydrogenase release. Compound 15 was equipotent with flunarizine, a reference compound in both neuroprotect ion assays.