Biochemical and pharmacological characterization of the putative dopamine autoreceptor agonist benzopyranopyridine, CGS 15873A

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 ED50 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 [3H] ADTN from dopamine recognition sites in a biphasic manner with IC50 values of 6 and 234 nM, respectively. At the dopamine D2 receptor defined by [3H] spiperone binding, CGS 15873A had an IC50 value of 234 nM. The compound had negligible activity (IC50 > 1 m̈M) in binding assays for dopamine D1, serotonin (5HT1A, 5HT1B, 5HT2), and α1‐adrenergic binding sites. Moderate activity was, however, observed in α2‐adrenoceptor binding (IC50 = 77 nM). CGS 15873A had a weak effect on stereotyped behavior (ED50 > 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 α2 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.