Comparison of pyrrolidinyl and piperidinyl benzamides for their anticonvulsant activity and inhibitory action on sodium channel.

Abstract

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.

• Authors: Y Zhu, W B Im, R A Lewis, P F VonVoigtlander
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 106 Issue 1 Pg. 49-54 (May 1992) ISSN: 0007-1188 [Print] England
• PMID: 1324068 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Anticonvulsants
• Cyclohexanes
• Piperidines
• Pyrrolidines
• Sodium Channels
• U 49132E
• U 49524E
• Sodium
• U 54494A

Topics

• Animals
• Anticonvulsants (pharmacology)
• Cyclohexanes (pharmacology)
• Injections, Intraperitoneal
• Male
• Mice
• Neuroblastoma
• Piperidines (pharmacology)
• Pyrrolidines (pharmacology)
• Seizures (drug therapy)
• Sodium (metabolism)
• Sodium Channels (drug effects, metabolism)
• Tumor Cells, Cultured