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)
Rizzi
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Department of Pharmacology, Boehringer Ingelheim Italia, Milan.
Prudentino
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Giraldo
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D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001562:Benzimidazoles / Q000009:adverse effects / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000009:adverse effects / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002491:Central Nervous System Agents / Q000009:adverse effects / Q000494:pharmacology*; D004285:Dogs; D004298:Dopamine / Q000502:physiology; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D009184:Mydriatics / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010095:Oxotremorine / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D012110:Reserpine / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000502:physiology; D012702:Serotonin Antagonists / Q000009:adverse effects / Q000494:pharmacology*; D013239:Stereotyped Behavior / Q000187:drug effects
D001562:Benzimidazoles; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002491:Central Nervous System Agents; D009184:Mydriatics; D018377:Neurotransmitter Agents; D012702:Serotonin Antagonists; C070191:itasetron; D012701:Serotonin; D010095:Oxotremorine; D012110:Reserpine; D004298:Dopamine