IN-VITRO CHARACTERIZATION OF TRIPITRAMINE, A POLYMETHYLENE TETRAAMINEDISPLAYING HIGH SELECTIVITY AND AFFINITY FOR MUSCARINIC M(2) RECEPTORS

1 The antimuscarinic effects of tripitramine were investigated in vitr o in isolated driven left (force) and spontaneously beating right (for ce and rate) atria as well as in the ileum of guinea-pig and rat and i n the trachea and lung strip of guinea-pig and compared with the effec ts of methoctramine. 2 Tripitramine was a potent competitive antagonis t of muscarinic M(2) receptors in right and left atria. The pA(2) valu es ranged from 9.14 to 9.85. However, in the guinea-pig and rat left a tria but not in guinea-pig right atria, tripitramine at lower concentr ations (3-10 nM) produced a less than proportional displacement to the right of agonist-induced responses owing to the presence of a possibl e saturable removal process. 3 Tripitramine was about three orders of magnitude less potent in ileal and tracheal than in atrial preparation s (pA(2) values ranging from 6.34 to 6.81) which makes it more potent and more selective than methoctramine. 4 Another intriguing finding wa s the observation that the pA(2) value of 7.91 observed for tripitrami ne in guinea-pig lung does not correlate with that found at both musca rinic M(2) and M(3) receptor subtypes, which. clearly indicates that t he contraction of guinea-pig lung strip is not mediated by these musca rinic receptor subtypes. 5 A combination of tripitramine with atropine resulted in addition of the dose-ratios for left atria as required fo r two antagonists interacting competitively with the same receptor sit e, whereas the same combination gave a supra-additive antagonism on gu inea-pig ileum which suggests that tripitramine interacts with a secon d interdependent site. 6 Tripitramine was more specific than methoctra mine since, in addition to muscarinic receptors, it inhibited only fro g rectus abdominis muscular (pIC(50) value of 6.14) and rat duodenum n euronal (pIC(50) value of 4.87) nicotinic receptors among receptor sys tems investigated, namely alpha(1)-, alpha(2)-, and beta(1)-adrenocept ors, H-1- and H-2-histamine receptors, and muscular and neuronal nicot inic receptors.