Inhibition of [3H]-MK801 binding and protection against NMDA-induced lethality in mice by a series of imipramine analogs.

A series of imipramine analogs were tested for inhibition of [3H]-MK801 binding and for their ability to protect against NMDA-induced lethality in mice. The structure-activity relationship (SAR) for the inhibition of [3H]-MK801 binding found primary amines on short linkers to be optimum. For protection against NMDA lethality, compounds containing an unsaturated link to a cyclic amine were the most potent analogs tested. Possible explanations for the lack of correlation observed are briefly discussed.

Synthesis and pharmacological evaluation of a major metabolite of ameltolide, a potent anticonvulsant.

The 4-aminobenzamides have provided several anticonvulsants that have been extensively investigated. Ameltolide, 4-amino-N-(2,6-dimethylphenyl)benzamide (compound 2,LY201116), is the most potent analogue studied to date. This drug is inactivated in vivo by metabolic N-acetylation and addition of a hydroxy moiety to one of the methyl substituents, resulting in compound 7,N-[4-[[[2-(hydroxymethyl)-6- methylphenyl] amino] carbonyl] phenyl] acetamide. This metabolite was prepared in five steps from a readily available starting material. Compound 7 and its nonacetylated analogue 6 were compared to ameltolide as anticonvulsants. After oral administration to mice, the MES ED50 values of ameltolide, 6, and 7 were 1.4, 10.9, and greater than 100 mg/kg, respectively, demonstrating that hydroxylation and acetylation dramatically decrease the anticonvulsant potency of ameltolide. This rank order of MES anticonvulsant potency was also seen after iv administration to mice, suggesting that these data reflect intrinsic pharmacological activities. After oral administration of 2.0 mg/kg of ameltolide to mice, parent drug, N-acetyl metabolite 3, and the hydroxy metabolite 7 were detected in plasma; the Cmax values were 572, 387, and 73 ng/mL, respectively. Compound 7 was the primary metabolite excreted in urine. These data indicate that 7 is a major metabolite of ameltolide, but does not contribute significantly to the pharmacological effects seen after administration of ameltolide to mice.

Pharmacology of LY201409, a potent benzamide anticonvulsant.

LY201116 [4-amino-N-(2,6-dimethylphenyl)benzamide], an effective anticonvulsant in several animal models, is rapidly metabolized by N-acetylation in rats, mice and monkeys. In an attempt to preclude metabolic N-acetylation sterically, we investigated LY201409, an analogue possessing two methyl groups ortho to the 4-amino substituent. This structural modification successfully altered the metabolic pathway, and LY201409 displayed potent anticonvulsant activity. LY201409 antagonized maximal electroshock (MES)-induced seizures with ED50 values of 16.2 and 4.2 mg/kg after oral administration to mice and rats, respectively. The compound did not effectively antagonize seizures induced by a variety of chemical convulsants in rats, but did block pentylenetetrazol-induced seizures in mice. Thus, among the classic anticonvulsants, the profile of phenytoin most closely resembles that of LY201409. Studies conducted with the rotorod and horizontal screen assays in mice and behavioral studies in rats suggested that doses of LY201409 that produced CNS side-effects such as sedation or ataxia were well separated from the anti-MES doses. LY201409 was a potent, dose-dependent potentiator of hexobarbital-induced sleeping time in mice. Oral administration of 6.0 mg/kg led to a 372% increase in sleep time relative to control values. Although LY201409 is a potent and effective anticonvulsant, it is also one of the most potent potentiators of hexobarbital-induced sleep time yet described.

Anticonvulsant effects of a novel aminobenzamide (LY201116) in mice.

The drug 4-amino-N-(2,6-dimethylphenyl)benzamide(LY201116) is a potent and selective anticonvulsant in the maximal electric shock test in mice. The ED50 values after oral and intravenous administration were 1.7 mg/kg and 0.51 mg/kg, respectively. For comparison, the oral and intravenous ED50 values for the anticonvulsant phenytoin which is selective for the maximal electric shock test were 9.1 and 8.5 mg/kg, respectively. After oral administration, LY201116 had a protective index (ED50 to produce neurological impairment, divided by ED50 on the maximal electric shock) of 13.5. After 4 days of administration, there was no evidence of the development of tolerance to the anticonvulsant effects of LY201116. The hexobarbital-induced sleeping time was not significantly affected by either acute or chronic administration of LY201116 for 4 days. In combination studies with the anticonvulsants phenytoin and carbamazepine which are selective for the maximal electric shock test, LY201116 produced dose-additive effects which suggest that it produces its anticonvulsant action through the same mechanism of action as these prototype anticonvulsants.

N-methyl-D-aspartic acid-induced lethality in mice: selective antagonism by phencyclidine-like drugs.

N-Methyl-D-aspartic acid (NMDA) produced a dose-related increase in lethality in mice, with 200 mg/kg (i.p.) effecting 100% lethality. Upon daily dosing, acutely sublethal doses of NMDA produced deaths. This NMDA-induced lethality was stereoselective; N-methyl-L-aspartic acid had no effects at doses as high as 400 mg/kg. Moderate doses of phencyclidine (PCP) and drugs having PCP-like behavioral effects blocked the NMDA-induced lethality. Other classes of psychoactive drugs, including opioids, anticonvulsants and antipsychotics, were ineffective in preventing NMDA-induced lethality. The potency of PCP-like drugs to block the NMDA-induced lethality correlates highly with the dose necessary to produce PCP-like catalepsy and PCP-like discrimination in pigeons. These data support the hypothesis that PCP-like drugs produce many of their effects by impairing the normal functioning of the NMDA-defined excitatory neurotransmitter receptor in the central nervous system.

Pharmacological effects of enantiomers of 4-amino-N-(alpha-methylbenzyl)benzamide, a chemically novel anticonvulsant.

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.