EFFECTS ON GENERAL BEHAVIOR AND NEUROTRANSMITTER FUNCTIONS OF A NEW 5-HYDROXYTRYPTAMINE(3) RECEPTOR ANTAGONIST WITH POTENTIAL THERAPEUTIC RELEVANCE IN CENTRAL-NERVOUS-SYSTEM DISTURBANCES

1. The general pharmacology of DAU 6215 (N- (endo-8-methyl-8-azabicycl o(3.2.1)oct-3-yl) -2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide hy drochloride, CAS 127618-28-4), a new 5-hyaroxytryptamine3 (5-HT3) rece ptor antagonist, was investigated for a preliminary evaluation of its toxicity and possible side-effects related to interferences with neuro transmitter functions. 2. In vitro studies - receptor binding: DAU 621 5 showed a high affinity for 5-HT3 receptors (Ki, nmol/l: 3.8) without any significant affinity for other serotonergic, adrenergic or dopami nergic receptors. A certain affinity was found for muscarinic (M) rece ptors (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 (1 00 mg/kg p.o. and 30 mg/kg i. v. ). A t lethal doses, deaths occurred with signs of central nervous system excitation, like tremors, twitche s and convulsions. Survived mice exhibited a complete recovery from sy mptoms within 1 h from administration. DAU 6215 did not exhibit any ef fect either on motor and exploratory activity or in the traction rest in mice up to 30 mg/kg ip. In the open field test in rats, DAU 6215 (0 .01 and 10 mg/kg p.o.) failed to modify the behavioural parameters con sidered, with the exception of a decrease in defecations al 10 mg/kg. 4. In vivo studies - neurotransmitter functions: a) Monoaminergic tran smission: reserpine-induced hypothermia in mice was not antagonized by DAU 6215 (0.01-1 mg/kg i.p.). The compound did not affect per se basa l temperature. b) Serotonergic transmission: DAU 6215 (1 mg/kg i.p.) c aused a slight inhibition of 5-hydroxytryptophan- and quipazine-induce d head twitches in mice and failed to affect head twitches induced by +/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) . Dopaminergic transmission: apomorphine- and d-amphetamine-induced st ereotyped behaviour was not significantly affected by DAU 6215 (0.1 an d 10 mg/kg ip.). d) Cholinergic transmission: DAU 6215 caused mydriasi s in rats (ED200 = 867 mug/kg i.v.; atropine ED200 = 5.6 mug/kg i. v. ), inhibition of meal-induced salivation in dogs (at 3000 mug/kg i.v.: 58 % inhibition; atropine 10 mug/kg i. v.: 76 % inhibition), inhibiti on of oxotremorine-induced salivation in rats (ID50 = 2333 ug/kg i. v. ; atropine ID50 = 8.6 mug/kg iv.). DAU 6215 did not affect the miotic reflex in dogs up to 3000 mug/kg iv. (atropine: 200 % increase of pupi l size at 100 mug/kg i. v.) and oxo-tremorine-induced tremors in rats up to 5500 mug/kg i. v. (atropine: ID50 = 453 mug/kg i. v. ). 5. In co nclusion, DAU 6215 exerts a low neurotoxic activity and does not inter fere with neurotransmitter functions when evaluated with general pharm acological procedures. The only appreciable interaction concerns musca rinic receptor-mediated functions. However, this occurs at doses great ly higher than those at which DAU 6215 is active in specific pharmacod ynamic tests related to 5-HT3 receptor antagonism in the same animal s pecies.