title: Partial dopamine-agonistic and atypical neuroleptic properties of the amino-ergolines SDZ 208-911 and SDZ 208-912.
abstract: The aminoergolines SDZ 208-911 [N-[(8-alpha)-2,6-dimethylergoline-8-yl]-2,2- dimethylpropanamide] and SDZ 208-912 [N-[8-alpha)-2-chloro-6-methylergoline-8-yl]- 2,2-dimethylpropanamide] exhibit nonclassical, neuroleptic-like properties in rodents. Thus, they are equipotent to haloperidol as inhibitors of apomorphine-induced gnawing behavior and conditioned avoidance responding, but are essentially devoid of cataleptogenic activity. In addition, they show high affinity for central D-2 receptors in vitro and elevate striatal homovanillic acid levels. In contrast to haloperidol, however, SDZ 208-911 and 208-912 strongly inhibit prolactin secretion and induce contralateral circling behavior in 6-hydroxydopamine-lesioned animals. These profiles are consistent with the drugs exhibiting varying degrees of partial agonistic activity at dopamine D-2 receptors, with SDZ 208-911 being considerably more agonistic than SDZ 208-912. Support for this contention stems from the ability of SDZ 208-911 to reduce the elevation of striatal L-dopa formation induced by gamma-butyrolactone, and SDZ 208-912's partial reversal of apomorphine's inhibitory action on gamma-butyrolactone activity. SDZ 208-911's effects are reduced after the partial alkylation of D-2 receptors with N-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline, confirming its partial agonistic properties. SDZ 208-911 and SDZ 208-912 could be effective against both the positive and negative symptoms of schizophrenia, while exhibiting a reduced incidence of dystonic and parkinsonian side-effects. In addition, their clinical testing might throw more light on the central dopaminergic status of schizophrenic subjects.
authors.affiliation: Sandoz Research Institute, Berne Ltd. Berne, Switzerland.
authors.forename: D M
authors.initials: DM
authors.lastname: Coward
authors.forename: A K
authors.initials: AK
authors.lastname: Dixon
authors.forename: S
authors.initials: S
authors.lastname: Urwyler
authors.forename: T G
authors.initials: TG
authors.lastname: White
authors.forename: A
authors.initials: A
authors.lastname: Enz
authors.forename: M
authors.initials: M
authors.lastname: Karobath
authors.forename: G
authors.initials: G
authors.lastname: Shearman
mesh_terms: D015107:4-Butyrolactone / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced; D004298:Dopamine / Q000032:analysis / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D004873:Ergolines / Q000494:pharmacology*; D005260:Female; D008297:Male; D011388:Prolactin / Q000097:blood; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000032:analysis / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D015259:Dopamine Agents; D004873:Ergolines; D011954:Receptors, Dopamine; C062737:N-(2,6-dimethylergoline-8-yl)-2,2-dimethylpropanamide; C059362:N-(2-chloro-6-methylergoline-8-yl)-2,2-dimethylpropanamide; D011388:Prolactin; D001058:Apomorphine; D015107:4-Butyrolactone; D004298:Dopamine