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Blockade of 5‐HT 3 receptor‐mediated currents in dissociated frog sensory neurones by benzoxazine derivative, Y‐25130
Author(s) -
Yakushiji Takashi,
Akaike Norio
Publication year - 1992
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1992.tb14536.x
Subject(s) - reversal potential , chemistry , biophysics , patch clamp , agonist , membrane potential , voltage clamp , 5 ht receptor , conductance , receptor , current clamp , electrophysiology , endocrinology , medicine , serotonin , biochemistry , biology , mathematics , combinatorics
1 The effect of Y‐25130, ((±)‐N‐(1‐azabicyclo[2.2.2]oct‐3‐yl)‐6‐chloro‐4‐methyl‐3‐oxo‐3,4‐dihydro‐2H‐1,4‐benzoxazine‐8‐carboxamide hydrochloride), a high affinity 5‐hydroxytryptamine 3 (5‐HT 3 ) receptor ligand, was examined on the 5‐HT‐induced response in dissociated frog dorsal root ganglion (DRG) neurones by use of the extremely rapid concentration‐jump (“concentration‐clamp’) and the conventional whole‐cell patch‐clamp techniques. 2 5‐HT induced a rapid transient inward current associated with an increase in membrane conductance at a holding potential of — 70 mV. The current amplitude increased sigmoidally as 5‐HT concentration increased. The half‐maximum value ( K a ) and the Hill coefficient estimated from the concentration‐response curve were 1.7 × 10 −5 m and 1.7, respectively. 3 The current‐voltage ( I—V ) relationship of 5‐HT‐induced current ( I 5‐HT ) showed inward rectification at potentials more positive than — 40 mV. The reversal potential ( E 5‐HT ) was — 11 mV. The E 5 ‐HT value was unaffected by total replacement of intracellular K + by Cs + , indicating that the 5‐HT‐gated channels might be large cation channels. 4 Both the activation and inactivation phases of I 5‐HT were single exponentials. The time constants of activation and inactivation (τ a and τ i ) decreased with increasing 5‐HT concentration. 5 The 5‐HT response was mimicked by a selective 5‐HT 3 receptor agonist, 2‐methyl‐5‐HT, but the maximum response induced was approximately 25% that of 5‐HT. The 5‐HT response was reversibly antagonized by the 5‐HT 3 receptor antagonists, ICS 205–930, metoclopramide and Y‐25130, but not by a 5‐HT 1A receptor antagonist, spiperone, and a 5‐HT 2 receptor antagonist, ketanserin. The half‐inhibition concentrations (IC 50 ) were 4.9 × 10 −10 m for Y‐25130, 4.8 × 10 −10 m for ICS 205–930 and 8.6 × 10 −9 m for metoclopramide. 6 Y‐25130 (5 × 10 −10 m ) caused a rightward shift of the concentration‐response curve for 5‐HT while decreasing the maximum response. 7 The results suggest that Y‐25130 is a potent antagonist of the 5‐HT 3 receptor‐channel complex.