Protection against the lethal effects of pentobarbital in mice by a benzodiazepine receptor inverse agonist, 6,7-dimethoxy-4-ethyl-3-carbomethoxy-beta-carboline.

Abstract

The benzodiazepine receptor inverse agonist 6,7-dimethoxy4-ethyl-3-carbomethoxy-i-carboline (DMCM) (1.5-15 mg/kg) was administered to mice 5 min after a lethal (LD94) injection of pentobarbital. DMCM (1.5-5 mg/kg) increased short-term (1 h) survival in a dose-dependent fashion, with an optimum survival rate more than five times greater than mice receiving pentobarbital alone. Statistically significant increases in longterm (24 h) survival were also observed after both 5 and 10 mg/ kg of DMCM (34 and 33%, respectively) compared with animals receiving pentobarbital alone (6%). Two doses of DMCM (5 and 2.5 mg/kg, respectively) administered 55 min apart produced an even greater increase (58%) in 24-h survival rates. Doses of DMCM that increased 1-and 24-h survival were not lethal when administered alone, and were below the dose that produced convulsions in 50% (CD50) of the animals. The protective effects of DMCM were blocked by pretreatment with the benzodiazepine receptor antagonist ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazoll,5ajll,4]benzodiazodiazepine-3-arboxylate (Ro 15-1788), which suggests the effects of DMCM are mediated through the benzodiazepine receptor. These findings suggest that DMCM or another benzodiazepine receptor ligand with full inverse agonist qualities could prove effective as an antidote for barbiturate intoxication in man.

Design, synthesis, and subtype selectivity of 3,6-disubstituted β-carbolines at Bz/GABA(A)ergic receptors. SAR and studies directed toward agents for treatment of alcohol abuse

“…Some of these agents act on the BzR to induce effects that are functionally opposite (inverse agonists/antagonists) to those of classical BDZs. Consequently, the affinities of a wide variety of β-carbolines have been reported on synaptosomal membranes from this laboratory,60,72,78,80,81,86–90 and the laboratories of others,91–96 and this prompted the study of the binding affinities of a series of β-carbolines67 at 5 recombinant GABA A /BzR subtypes (α 1 β 3 γ 2 , α 2 β 3 γ 2 , α 3 β 3 γ 2 , α 5 β 3 γ 2 and α 6 β 3 γ 2 ) expressed from recombinant human cell lines 91,97. In general, this series of β-carboline ligands exhibited some selectivity at α 1 receptor subtypes including βCCt ( 1 ) and 3-PBC ( 2 ) 2,3.…”

β-Carboline Alkaloids: Biochemical and Pharmacological Functions

“…Enhance animal performance [130][131] ZK-93426 Increase of alertness and improve attention in man [132] DMCM 1. Inverse agonist [133] 2. Prevention lethality from overdoses of pentobarbital [133] 3-HMC Reduce of pentobarbital-induced decrements in cerebral blood flow and oxygen consumption [134] 3-Ethoxy--carboline Partial inverse agonist [135][136] ZK 93423 Agonist [139] ZK 91296 Anticonvulsant [138] 3-Ethylamino--carboline Proconvulsant activity in Papio papio baboons [79] -CMC Selectively antagonize the sedative effects of diazepam [79] FG 7142…”

“…Moreover, the ethyl 5-isopropoxy-4-methyl--carboline-3-carboxylate (ZK-93426, 19) was shown to increase alertness and improve attention in human [132]. The BZ inverse agonist 6,7-dimethoxy-4-ethyl-3-carbomethoxy--carboline (DMCM, 20) was reported to prevent lethality from overdoses of pentobarbital [133] and the 3-(hydroxymethyl)--carboline (3-HMC, 18) reduced pentobarbital-induced decrements in cerebral blood flow and oxygen consumption [134]. 3-Ethoxy--carboline was proven to be a potent, long-lived, water-soluble partial inverse agonist [135][136].…”

Central nervous system effects of the imidazodiazepine Ro 15‐4513

“…The basis for the different results across labs is not yet clear. It would not be unprecedented to find that an "inverse agonist" could protect against the lethal effects of a sedative drug (for example, Havoundjian et al [1987]). The clinical relevance of a drug to block the toxic effect of ethanol would be profound.…”