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In vitro characterization of tripitramine, a polymethylene tetraamine displaying high selectivity and affinity for muscarinic M 2 receptors
Author(s) -
Chiarini A.,
Budriesi R.,
Bolognesi M.L.,
Minarini A.,
Melchiorre C.
Publication year - 1995
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.1476-5381.1995.tb13378.x
Subject(s) - methoctramine , muscarinic acetylcholine receptor , guinea pig , agonist , atropine , receptor , ileum , medicine , endocrinology , chemistry , contraction (grammar) , muscarinic acetylcholine receptor m2 , biology
1 The antimuscarinic effects of tripitramine were investigated in vitro in isolated driven left (force) and spontaneously beating right (force and rate) atria as well as in the ileum of guinea‐pig and rat and in the trachea and lung strip of guinea‐pig and compared with the effects of methoctramine. 2 Tripitramine was a potent competitive antagonist of muscarinic M 2 receptors in right and left atria. The pA 2 values ranged from 9.14 to 9.85. However, in the guinea‐pig and rat left atria but not in guinea‐pig right atria, tripitramine at lower concentrations (3–10 nM) produced a less than proportional displacement to the right of agonist‐induced responses owing to the presence of a possible saturable removal process. 3 Tripitramine was about three orders of magnitude less potent in ileal and tracheal than in atrial preparations (pA 2 values ranging from 6.34 to 6.81) which makes it more potent and more selective than methoctramine. 4 Another intriguing finding was the observation that the pA 2 value of 7.91 observed for tripitramine in guinea‐pig lung does not correlate with that found at both muscarinic M 2 and M 3 receptor subtypes, which clearly indicates that the contraction of guinea‐pig lung strip is not mediated by these muscarinic receptor subtypes. 5 A combination of tripitramine with atropine resulted in addition of the dose‐ratios for left atria as required for two antagonists interacting competitively with the same receptor site, whereas the same combination gave a supra‐additive antagonism on guinea‐pig ileum which suggests that tripitramine interacts with a second interdependent site. 6 Tripitramine was more specific than methoctramine since, in addition to muscarinic receptors, it inhibited only frog rectus abdominis muscular (pIC 50 value of 6.14) and rat duodenum neuronal (pIC 50 value of 4.87) nicotinic receptors among receptor systems investigated, namely α 1‐ , α 1‐ , and β 1‐ adrenoceptors, H 1‐ and H 2 ‐histamine receptors, and muscular and neuronal nicotinic receptors.