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Biochemical and pharmacological characterization of the putative dopamine autoreceptor agonist benzopyranopyridine, CGS 15873A
Author(s) -
Glaeser Bruce S.,
Liebman Jeffrey M.,
Sills Matthew A.,
Hutchison Alan J.,
Lovell Richard A.,
Welch James,
Jarvis Michael F.,
Bennett Debra A.,
Williams Michael
Publication year - 1989
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430180303
Subject(s) - autoreceptor , agonist , dopamine , chemistry , dopamine agonist , spiperone , endocrinology , medicine , dopamine receptor , receptor , biochemistry , biology
The substituted benzopyranopyridine, CGS 15873A (± trans‐1,3,4,4a,4,10b‐hexahydro‐4‐propyl‐2H‐[1]benzopyrano[3,4‐b]‐pyridine‐70olmonohydrochloride), was evaluated for its dopamine receptor agonist and other properties in biochemical and behavioral test procedures. In the γ‐butyrolactone (GBL) model of dopamine autoreceptor function, CGS 15873A i.p. had an ED 50 value of 1.83 m̈mole/kg indicating that the compound had dopamine autoreceptor agonist activity. The corresponding p.o. value was 2.11 m̈mole/kg, indicating reasonable oral bioavailability. The compound exhibited a shallow competition curve in displacing [ 3 H] ADTN from dopamine recognition sites in a biphasic manner with IC 50 values of 6 and 234 nM, respectively. At the dopamine D 2 receptor defined by [ 3 H] spiperone binding, CGS 15873A had an IC 50 value of 234 nM. The compound had negligible activity (IC 50 > 1 m̈M) in binding assays for dopamine D 1 , serotonin (5HT 1A , 5HT 1B , 5HT 2 ), and α 1 ‐adrenergic binding sites. Moderate activity was, however, observed in α 2 ‐adrenoceptor binding (IC 50 = 77 nM). CGS 15873A had a weak effect on stereotyped behavior (ED 50 > 106 μmole/kg i.p.), an indication of postsynaptic activity, but showed partial generalization in a clonidine discrimination paradigm, indicating that it was a partiall α 2 agonist. CGs 15873A appears to be a relatively selective dopmine agonist with preferentia activity at presynaptic autoreceptors and, as such, may represent a novel agent for treatment of disorders such as schizophreniaand Parkinsonism.