Behavioural pharmacology of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro- 1H-dibenz[2,3:6,7]oxepino-[4,5-c]pyrrolidine maleate, a compound interacting with dopaminergic and serotonergic receptors.
trans-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1H- dibenz[2,3:6,7]oxepinol[4,5-c]pyrrolidine maleate (Org 5222) is a new compound with effects on animal behaviour indicating strong antipsychotic potential based on antagonism of dopaminergic and serotonergic effects. The compound inhibits apomorphine-induced climbing behaviour, mouse locomotor activity, rat activity in an open field, shuttle box behaviour in rats, pergolide induced circling in 6-hydroxydopamine(6-OHDA) lesioned rats, serotonin agonist-induced forepaw treading, head shakes and penile erections. The compound is less effective in inducing catalepsy, and antagonising SKF-38393 (tetrahydro- 1-phenyl-1H-3-benzazepine-7,8-diol HCl)-induced circling in 6-OHDA-lesioned rats and it does not induce perioral movements in rats. Based on these data and the neurochemical profile of the compound it was decided that this compound merits clinical investigation in a programme aiming for an effective antipsychotic agent with reduced risks of extrapyramidal side-effects.
Broekkamp
C L
CL
Scientific Development Group, Organon International B.V., Pharma Division Akzo, Oss, The Netherlands.
De Graaf
J S
JS
van Delft
A M
AM
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D002375:Catalepsy / Q000139:chemically induced; D002746:Chlorpromazine / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D003220:Conflict, Psychological; D003986:Dibenzocycloheptenes; D003990:Dibenzoxepins / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*; D013239:Stereotyped Behavior / Q000187:drug effects
D014150:Antipsychotic Agents; D003986:Dibenzocycloheptenes; D003990:Dibenzoxepins; D006576:Heterocyclic Compounds, 4 or More Rings; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D003024:Clozapine; D006220:Haloperidol; C522667:asenapine; D002746:Chlorpromazine