BLOCKING EFFECTS OF PROMETHAZINE, TRIPROLIDINE AND THEIR ANALOGS ON THE EXCITATION CAUSED BY THE PEPTIDE, ACHATIN-I

An Achatina endogenous tetrapeptide, achatin-I (Gly-D-Phe-Ala-Asp), ap plied by brief pressure, produced an inward current (I-in) on an Achat ina giant neurone type, PON (periodically oscillating neurone). Promet hazine, triprolidine and their analogues tested, applied by perfusion, showed a tendency to inhibit the I-in, 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 prometha zine analogues, RP 6497 and RP 6549 (the structures are shown in Fig. 1), inhibited the I-in 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-configurati on. 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-p yrrolidino weakened the effects. The two triprolidine analogues, Trip Der 3 and Trip Der 6 (the structures in Fig. 2), inhibited the I-in in an uncompetitive manner.