A novel water-soluble dopamine-2 antagonist with anticholinesterase activity in gastrointestinal motor activity. Comparison with domperidone and neostigmine.

A novel water-soluble dopamine-2 antagonist, N-[4-[2-(dimethylamino) ethoxy]benzyl]-3,4-dimethoxybenzamide hydrochloride (HSR-803) was synthesized and assayed for its gastrointestinal smooth muscle stimulating activity in vivo and in vitro. In the in vivo study, gastrointestinal contractile activity was measured by means of chronically implanted force transducers in conscious dogs; it was found that HSR-803 at 3.0 mg/kg IV probably stimulated gastric contractile force twice during the digestive state and significantly antagonized dopamine-(1.0 mg/kg per hour) inhibited gastric contractions in doses of 0.3, 1, and 3 mg/kg IV. With a background IV infusion of HSR-803 at 3 mg/kg per hour, the contraction-stimulating activity of acetylcholine (0.05 mg/kg per minute) was greatly enhanced while the response to bethanechol was not changed. As a result, HSR-803 was found to have a strong anticholinesterase activity besides the antidopamine-2 activity; i.e., the anticholinesterase activity of HSR-803 at 3 mg/kg per hour was equivalent to that of neostigmine at 10 micrograms/kg per hour, and dopamine-2 antagonistic activity of HSR-803 was similar to that of domperidone on a weight basis. No symptom suggesting actions on the central nervous system was noticed in HSR-803 up to 10 mg/kg IV in conscious dogs. In the in vitro study, HSR-803 inhibited cholinesterase dose-dependently, and IC50 was 2.9 x 10(-6) mol/L, while those of neostigmine and domperidone were 2.3 x 10(-8) mol/L and 1.7 x 10(-5) mol/L, respectively. In conclusion, HSR-803 stimulates endogenous acetylcholine release by antagonizing the dopamine-2 receptor on the postsynaptic cholinergic neurons, and the anticholinesterase activity of HSR-803 may cause the released acetylcholine to accumulate at cholinergic receptor sites. Thus, HSR-803 is potentially capable of enhancing cholinergic activity in the gastrointestinal region.