MODE OF ANTAGONISM OF METHOCTRAMINE, AF-DX-116 AND HEXAHYDROSILADIFENIDOL IN GUINEA-PIG LEFT ATRIUM AND ILEUM - COMPARISON OF SCHILD AND RESULTANT ANALYSIS
C. Boselli et E. Grana, MODE OF ANTAGONISM OF METHOCTRAMINE, AF-DX-116 AND HEXAHYDROSILADIFENIDOL IN GUINEA-PIG LEFT ATRIUM AND ILEUM - COMPARISON OF SCHILD AND RESULTANT ANALYSIS, Journal of autonomic pharmacology, 15(2), 1995, pp. 115-127
1 Methoctramine, AF-DX 116 and hexahydrosiladifenidol (HHSiD) are the
muscarinic antagonists most widely used to study muscarinic receptor s
ubtypes. 2 The present study was undertaken to examine the mode of ant
agonism of these compounds in guinea-pig left atrium and ileum by comp
arison of the Schild and resultant analysis. With this method the effe
ct of various concentrations of the test antagonist on the antagonism
produced by specific concentrations of a reference antagonist was meas
ured and the equilibrium dissociation constant of the test antagonist-
receptor complex estimated. Atropine was used for comparative purposes
and scopolamine as the reference antagonist. 3 At the cardiac level t
he affinity values obtained by Schild and resultant analysis for metho
ctramine and AF-DX 116, as for atropine, are very similar: these resul
ts indicate that the two cardio-selective antagonists and the non-sele
ctive antagonist, atropine, bind at a common site with the reference a
ntagonist scopolamine. The resultant plot for the ileo-selective HHSiD
has a slope considerably less than unity: this finding might indicate
that this antagonist binds to a site different from that of scopolami
ne and it should be considered like an allosteric antagonist. 4 At the
ileal level the affinity values obtained by Schild and resultant anal
ysis are identical for the ileo-selective antagonist HHSiD as for atro
pine but not for methoctramine and AF-DX 116. This indicates a mutual
binding site with scopolamine for HHSiD and atropine but not for the t
wo cardio-selective antagonists. However, it is worth emphasizing that
the difference between affinity values obtained by Schild and resulta
nt analysis is seen when relatively high concentrations are required:
a dual mode of interaction (both competitive and allosteric) could be
invoked.