Effects on general behaviour and neurotransmitter functions of a new 5-hydroxytryptamine3 receptor antagonist with potential therapeutic relevance in central nervous system disturbances.
1. The general pharmacology of DAU 6215 (N-(endo-8-methyl-8-azabicyclo(3.2.1) oct-3-yl)-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide hydrochloride, CAS 127618-28-4), a new 5-hydroxytryptamine3 (5-HT3) receptor antagonist, was investigated for a preliminary evaluation of its toxicity and possible side-effects related to interferences with neurotransmitter functions. 2. In vitro studies--receptor binding: DAU 6215 showed a high affinity for 5-HT3 receptors (Ki, nmol/l: 3.8) without any significant affinity for other serotonergic, adrenergic or dopaminergic receptors. A certain affinity was found for muscarinic (M) receptors (Ki, nmol/l: M1 = 95; M2 = 6,917; M3 = 181). 3. In vivo studies--general behaviour: In mice, DAU 6215 was well tolerated up to 100 mg/kg p.o. and 30 mg/kg i.v. The only noticeable symptom was mydriasis. No other major symptoms appeared up to the maximum non lethal doses (100 mg/kg p.o. and 30 mg/kg i.v.). At lethal doses, deaths occurred with signs of central nervous system excitation, like tremors, twitches and convulsions. Survived mice exhibited a complete recovery from symptoms within 1 h from administration. DAU 6215 did not exhibit any effect either on motor and exploratory activity or in the traction test in mice up to 30 mg/kg i.p. In the open field test in rats, DAU 6215 (0.01 and 10 mg/kg p.o.) failed to modify the behavioural parameters considered, with the exception of a decrease in defecations at 10 mg/kg. 4. In vivo studies--neurotransmitter functions: a) Monoaminergic transmission: reserpine-induced hypothermia in mice was not antagonized by DAU 6215 (0.01-1 mg/kg i.p.).(ABSTRACT TRUNCATED AT 250 WORDS)[1]References
- Effects on general behaviour and neurotransmitter functions of a new 5-hydroxytryptamine3 receptor antagonist with potential therapeutic relevance in central nervous system disturbances. Rizzi, C.A., Prudentino, A., Giraldo, E. Arzneimittel-Forschung. (1993) [Pubmed]
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