The potential antipsychotic activity of the partial dopamine receptor agonist (+)N-0437.
The (+) enantiomer of the very potent and selective dopamine D-2 agonist, 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0437), displays partial agonistic activity at dopamine D-2 receptors. In this study (+)N-0437 was investigated for its antagonistic activity at postsynaptic DA receptors in four behavioural tests which are commonly used to evaluate potential neuroleptic activity, i.e. d-amphetamine-induced stereotypy, passive avoidance responding, intracranial self-stimulation behaviour, and catalepsy. (+)N-0437 (25-50 mumol/kg) was active in the first three models, but did not cause catalepsy. Haloperidol, which was used as a reference compound for classical DA antagonists, showed clear activity in all four models at low doses (0.5-1.0 mumol/kg). (-)N-0437, a full D-2 agonist, displayed no activity in these behavioural models. These results suggest that (+)N-0437 could be used to examine the hypothesis that the use of partial agonists could provide a new treatment for schizophrenia.
Timmerman
W
W
Department of Medicinal Chemistry, University Centre for Pharmacy, Groningen, The Netherlands.
Tepper
P G
PG
Bohus
B G
BG
Horn
A S
AS
D000818:Animals; D014150:Antipsychotic Agents; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced / Q000503:physiopathology; D003913:Dextroamphetamine / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D012653:Self Stimulation / Q000187:drug effects; D013237:Stereoisomerism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
D014150:Antipsychotic Agents; D015259:Dopamine Agents; D009281:Naphthalenes; D011954:Receptors, Dopamine; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C047508:rotigotine; D006220:Haloperidol; D003913:Dextroamphetamine