TY - JOUR
T1 - Interactions of agonists with an allosteric antagonist at muscarinic acetylcholine M2 receptors
AU - Lanzafame, Alfred
AU - Christopoulos, Arthur
AU - Mitchelson, Fred
PY - 1996/11/28
Y1 - 1996/11/28
N2 - The interaction of heptane-1,7-bis(dimethyl-3'-phthalimidopropylammonium bromide) (C7/3'-phth), with several agonists, was investigated at the muscarinic M2 receptor in guinea-pig left atria. C7/3'-phth shifted concentration-response curves for the agonists, carbachol, oxotremorine-M and (+)-cis-dioxolane, to the right in a parallel fashion. Arunlakshana-Schild regressions of the data yielded slopes significantly different to unity, suggesting non-competitive antagonism. Non-linear regression analysis, using an equation based on allosteric modulation, gave quantitative estimates of co-operativity (α values) and the dissociation constant of C7/3'-phth (K(B)). In all cases, the K(B) estimates for C7/3'-phth were not significantly different. Increasing the carbachol contact time 10-fold did not significantly influence the K(B) or the α value obtained with C7/3'-phth. Changing from Krebs to Tyrode solution did not significantly alter the K(B) for C7/3'-phth, although α values obtained were consistently lower in Tyrode solution, suggesting that the allosteric action may be sensitive to buffer composition. A 4-fold higher degree of negative, heterotropic co-operativity between C7/3'-phth and agonists than between C7/3'-phth and competitive antagonists was also found.
AB - The interaction of heptane-1,7-bis(dimethyl-3'-phthalimidopropylammonium bromide) (C7/3'-phth), with several agonists, was investigated at the muscarinic M2 receptor in guinea-pig left atria. C7/3'-phth shifted concentration-response curves for the agonists, carbachol, oxotremorine-M and (+)-cis-dioxolane, to the right in a parallel fashion. Arunlakshana-Schild regressions of the data yielded slopes significantly different to unity, suggesting non-competitive antagonism. Non-linear regression analysis, using an equation based on allosteric modulation, gave quantitative estimates of co-operativity (α values) and the dissociation constant of C7/3'-phth (K(B)). In all cases, the K(B) estimates for C7/3'-phth were not significantly different. Increasing the carbachol contact time 10-fold did not significantly influence the K(B) or the α value obtained with C7/3'-phth. Changing from Krebs to Tyrode solution did not significantly alter the K(B) for C7/3'-phth, although α values obtained were consistently lower in Tyrode solution, suggesting that the allosteric action may be sensitive to buffer composition. A 4-fold higher degree of negative, heterotropic co-operativity between C7/3'-phth and agonists than between C7/3'-phth and competitive antagonists was also found.
KW - Bisquaternary allosteric antagonist
KW - Muscarinic acetylcholine receptor agonist
UR - http://www.scopus.com/inward/record.url?scp=0030605219&partnerID=8YFLogxK
U2 - 10.1016/S0014-2999(96)00639-5
DO - 10.1016/S0014-2999(96)00639-5
M3 - Article
C2 - 8982646
AN - SCOPUS:0030605219
SN - 0014-2999
VL - 316
SP - 27
EP - 32
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1
ER -