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: D M Coward, A K Dixon, S Urwyler, T G White, A Enz, M Karobath, G Shearman
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 252 Issue 1 Pg. 279-85 (Jan 1990) ISSN: 0022-3565 [Print] United States
• PMID: 1967646 (Publication Type: Journal Article)

Chemical References

• Antipsychotic Agents
• Dopamine Agents
• Ergolines
• Receptors, Dopamine
• N-(2,6-dimethylergoline-8-yl)-2,2-dimethylpropanamide
• N-(2-chloro-6-methylergoline-8-yl)-2,2-dimethylpropanamide
• Prolactin
• Apomorphine
• 4-Butyrolactone
• Dopamine

Topics

• 4-Butyrolactone (pharmacology)
• Animals
• Antipsychotic Agents (pharmacology)
• Apomorphine (pharmacology)
• Avoidance Learning (drug effects)
• Behavior, Animal (drug effects)
• Catalepsy (chemically induced)
• Dopamine (analysis, metabolism)
• Dopamine Agents (pharmacology)
• Ergolines (pharmacology)
• Female
• Male
• Prolactin (blood)
• Rats
• Rats, Inbred Strains
• Receptors, Dopamine (analysis, drug effects)