Pharmacological Effects of Enantiomers of 4‐Amino‐N‐(α‐methylbenzyl)Benzamide, a Chemically Novel Anticonvulsant

Abstract

LY 188544,S,R-4-amino-N-(alpha-methylbenzyl) benzamide, and its two stereoisomers are structurally novel anticonvulsants. The anticonvulsant profile of LY 188544 after intraperitoneal administration to mice was determined in standard anticonvulsant tests: maximal electric shock (MES), strychnine tonic-extensor, and threshold tests using pentylenetetrazol, picrotoxin, and bicuculline. In this series of tests, LY 188544 had good activity in the MES test and some activity in the three threshold tests. Thus, its profile of activity was most similar to that of phenobarbital, and less similar to that of phenytoin and carbamazepine. After oral administration to mice and rats, LY188544 was effective in the MES test, but did not provide complete protection in the threshold pentylenetetrazol test. When the individual stereoisomers, LY188545 (S isomer) and LY188546 (R isomer), were evaluated after oral administration, LY188545 was 2.2 times more potent than LY188546 against MES-induced seizures. However, when evaluated after intravenous administration, the potency difference was only 1.1. LY188546 was the least toxic in terms of neurological impairment. All compounds had good protective indexes (ratio between doses for neurological impairment and doses for anticonvulsant efficacy in the MES test). LY188545 and LY188546 potentiated hexobarbital sleeping time after acute administration but not after chronic (4-day) administration. Tolerance did not develop to the effects of LY188546 on MES or neurological impairment after 4 days of administration. These results suggest that LY188546 is a chemically novel anticonvulsant with a promising pharmacological profile.

N-Cyclohexylbenzamide

“…For biological applications of benzamides, see: Clark et al (1988); Leander et al (1988); Diouf et al (1997).…”

“…Benzamides are frequently used in the synthesis of new and potent anti-convulsant agents (Clark et al, 1988;Leander et al, 1988;Diouf et al, 1997). The structure of the title compound, (I), a benzamide derivative, is reported herein (Fig.…”

Design, synthesis, anticonvulsant screening and 5HT_1A/2Areceptor affinity of <i>N</i>(3)-substituted 2,4-imidazolidinediones and oxazolidinediones

“…Ameltolide (13), ralitoline (14), and some phthalimide derivatives (15) are the best examples with potent anticonvulsant activity in the MES test ( Figure 1). Ameltolide was developed by Eli Lilly (Indianapolis, IN, USA), which originated from the approach of Clark et al This research group isolated the 4-aminobenzamide pharmacophore, which subsequently led to the design of a number of new and potent anticonvulsant agents (16)(17)(18)(19)(20). Apart from the acetamide and propionamide nucleus, hydantoin and oxazolidine-2,4-dione are also one of the most commonly used antiepileptic pharmacophores.…”

“…Based on the above findings, in the present study our interest was focused to target the 5-HT 1A/2A receptor. Herein derivatives of 5-phenyloxazolidine-2,4-dione and 5,5-diphenyl hydantoin (these moieties are already well established prototypes for antiepileptic drugs) attached to piperazine and aniline derivatives via an acetamide linkage (18,20) have been synthesized. Various electron donating and electron-attracting groups in the para position of aniline and piperazine were synthesized.…”

Methyl 2-(4-chlorobenzamido)benzoate

“…For related structures, see: Gowda et al (2008); Zhou & Zheng (2007); Khan et al (2010). Benzamide derivatives are frequently used in the synthesis of new and effective anti-convulsant agents, see: Clark et al (1988); Leander et al (1988); Diouf et al (1997). For bond-length data, see: Allen et al (1987).…”