Blocking effects of promethazine, triprolidine and their analogues on the excitation caused by the peptide, achatin-I.

An Achatina endogenous tetrapeptide, achatin-I (Gly-D-Phe-Ala-Asp), applied by brief pressure, produced an inward current (Iin) on an Achatina giant neurone type, PON (periodically oscillating neurone). Promethazine, triprolidine and their analogues tested, applied by perfusion, showed a tendency to inhibit the Iin, suggesting that the effective structures vary to a wide extent. With respect to promethazine and its analogues, the presence of 2-bromo, 5-oxo, 3-dimethylsulfamido and 2-methoxy weakened the effects. 10-(2-methylamino-2-methylethyl) instead of 10-(2-dimethylamino-2-methylethyl) of promethazine and the azepine ring instead of phenothiazine ring potentiated the effects. From the dose (pressure duration)-response study of achatin-I, the two promethazine analogues, RP 6497 and RP 6549 (the structures are shown in Fig. 1), inhibited the Iin in partly competitive and partly noncompetitive manners. Regarding triprolidine and its analogues, the compounds in Z-configuration seemed to be more effective than those in E-configuration. The presence of 4-methyl in 1-phenyl, and 1-(4-pyridyl) instead of 1-(2-pyridyl) potentiated the effects. 3-Dimethylamino instead of 3-pyrrolidino weakened the effects. The two triprolidine analogues, Trip Der 3 and Trip Der 6 (the structures in Fig. 2), inhibited the Iin in an uncompetitive manner.