Comparison of pyrrolidinyl and piperidinyl benzamides for their anticonvulsant activity and inhibitory action on sodium channel.
1. A pair of benzamide analogues containing a pyrrolidinyl or piperidinyl group was examined for their anticonvulsant activity against the electroshock-induced seizures in mice and the ability to block the voltage-gated Na channel in N1E-115 cells, in comparison with the prototype compound, U-54494A, (+/-)-cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-ben zam ide , a potent anticonvulsant and a Na channel blocker. 2. The pyrrolidinyl benzamide (U-49524E) was found to be effective against the electroshock-induced seizures (ED50 = 35 mg kg-1, i.p.) whereas the benzamide with a piperidinyl moiety (U-49132E) was inactive (ED50 greater than 100 mg kg-1). 3. Using whole-cell patch clamp techniques we found that U-49132E was several times less potent, with an IC50 of 396 microM as compared to 118 microM for U-49524E at the holding potential of -80 mV, and was much slower in blocking Na channels with a half-time of 10.7 +/- 1.1 min vs. 2.2 +/- 0.4 min for its counterpart. 4. Qualitatively, their general modes of interaction with Na channels were similar to each other and to that of U-54494A in that they interacted with the resting and slowly-inactivated states of the channels and exhibited a use-dependent inhibition because of a slow recovery from the inactivated state in the presence of the drugs. 5. Comparison of their physicochemical properties, shows the less potent and slowly acting U-49132E is more hydrophobic and bulkier than U-49524E, but has the same pKa. This suggests that the drugs approach the Na channel through a narrow and hydrophilic pathway.6. Overall, this study underscores the importance of inhibiting the Na channel to the anticonvulsant activity of the benzamide compounds.
Zhu
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CNS Diseases Research, Upjohn Company, Kalamazoo, MI 49001.
Im
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Lewis
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VonVoigtlander
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D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D003510:Cyclohexanes / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D009447:Neuroblastoma; D010880:Piperidines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D012640:Seizures / Q000188:drug therapy; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000927:Anticonvulsants; D003510:Cyclohexanes; D010880:Piperidines; D011759:Pyrrolidines; D015222:Sodium Channels; C076240:U 49132E; C076241:U 49524E; D012964:Sodium; C054216:U 54494A