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British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1995 Apr;114(7):1507–1517. doi: 10.1111/j.1476-5381.1995.tb13378.x

In vitro characterization of tripitramine, a polymethylene tetraamine displaying high selectivity and affinity for muscarinic M2 receptors.

A Chiarini 1, R Budriesi 1, M L Bolognesi 1, A Minarini 1, C Melchiorre 1
PMCID: PMC1510296  PMID: 7606355

Abstract

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 M2 receptors in right and left atria. The pA2 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 (pA2 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 pA2 value of 7.91 observed for tripitramine in guinea-pig lung does not correlate with that found at both muscarinic M2 and M3 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 (pIC50 value of 6.14) and rat duodenum neuronal (pIC50 value of 4.87) nicotinic receptors among receptor systems investigated, namely alpha 1-, alpha 2-, and beta 1-adrenoceptors, H1- and H2-histamine receptors, and muscular and neuronal nicotinic receptors.

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Selected References

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  1. ARUNLAKSHANA O., SCHILD H. O. Some quantitative uses of drug antagonists. Br J Pharmacol Chemother. 1959 Mar;14(1):48–58. doi: 10.1111/j.1476-5381.1959.tb00928.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Anwar-ul S., Gilani H., Cobbin L. B. The cardio-selectivity of himbacine: a muscarine receptor antagonist. Naunyn Schmiedebergs Arch Pharmacol. 1986 Jan;332(1):16–20. doi: 10.1007/BF00633191. [DOI] [PubMed] [Google Scholar]
  3. Barlow R. B., Berry K. J., Glenton P. A., Nilolaou N. M., Soh K. S. A comparison of affinity constants for muscarine-sensitive acetylcholine receptors in guinea-pig atrial pacemaker cells at 29 degrees C and in ileum at 29 degrees C and 37 degrees C. Br J Pharmacol. 1976 Dec;58(4):613–620. doi: 10.1111/j.1476-5381.1976.tb08631.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bey P., Bolkenius F. N., Seiler N., Casara P. N-2,3-Butadienyl-1,4-butanediamine derivatives: potent irreversible inactivators of mammalian polyamine oxidase. J Med Chem. 1985 Jan;28(1):1–2. doi: 10.1021/jm00379a001. [DOI] [PubMed] [Google Scholar]
  5. Bognar I. T., Altes U., Beinhauer C., Kessler I., Fuder H. A muscarinic receptor different from the M1, M2, M3 and M4 subtypes mediates the contraction of the rabbit iris sphincter. Naunyn Schmiedebergs Arch Pharmacol. 1992 Jun;345(6):611–618. doi: 10.1007/BF00164573. [DOI] [PubMed] [Google Scholar]
  6. Bonner T. I. The molecular basis of muscarinic receptor diversity. Trends Neurosci. 1989 Apr;12(4):148–151. doi: 10.1016/0166-2236(89)90054-4. [DOI] [PubMed] [Google Scholar]
  7. Caulfield M. P., Brown D. A. Pharmacology of the putative M4 muscarinic receptor mediating Ca-current inhibition in neuroblastoma x glioma hybrid (NG 108-15) cells. Br J Pharmacol. 1991 Sep;104(1):39–44. doi: 10.1111/j.1476-5381.1991.tb12381.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Caulfield M. P. Muscarinic receptors--characterization, coupling and function. Pharmacol Ther. 1993 Jun;58(3):319–379. doi: 10.1016/0163-7258(93)90027-b. [DOI] [PubMed] [Google Scholar]
  9. Chess-Williams R. G., Broadley K. J., Sheridan D. J. Calculated and actual changes in beta-adrenoceptor number associated with increases in rat and guinea-pig cardiac sensitivity. J Pharm Pharmacol. 1986 Dec;38(12):902–906. doi: 10.1111/j.2042-7158.1986.tb03380.x. [DOI] [PubMed] [Google Scholar]
  10. Clark A. L., Mitchelson F. The inhibitory effect of gallamine on muscarinic receptors. Br J Pharmacol. 1976 Nov;58(3):323–331. doi: 10.1111/j.1476-5381.1976.tb07708.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Durant P. A., Shankley N. P., Welsh N. J., Black J. W. Pharmacological analysis of agonist-antagonist interactions at acetylcholine muscarinic receptors in a new urinary bladder assay. Br J Pharmacol. 1991 Sep;104(1):145–150. doi: 10.1111/j.1476-5381.1991.tb12399.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dörje F., Friebe T., Tacke R., Mutschler E., Lambrecht G. Novel pharmacological profile of muscarinic receptors mediating contraction of the guinea-pig uterus. Naunyn Schmiedebergs Arch Pharmacol. 1990 Sep;342(3):284–289. doi: 10.1007/BF00169439. [DOI] [PubMed] [Google Scholar]
  13. Dörje F., Wess J., Lambrecht G., Tacke R., Mutschler E., Brann M. R. Antagonist binding profiles of five cloned human muscarinic receptor subtypes. J Pharmacol Exp Ther. 1991 Feb;256(2):727–733. [PubMed] [Google Scholar]
  14. Eberlein W. G., Engel W., Mihm G., Rudolf K., Wetzel B., Entzeroth M., Mayer N., Doods H. N. Structure-activity relationships and pharmacological profile of selective tricyclic antimuscarinics. Trends Pharmacol Sci. 1989 Dec;Suppl:50–54. [PubMed] [Google Scholar]
  15. Eglen R. M., Michel A. D., Whiting R. L. Characterization of the muscarinic receptor subtype mediating contractions of the guinea-pig uterus. Br J Pharmacol. 1989 Mar;96(3):497–499. doi: 10.1111/j.1476-5381.1989.tb11843.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Eglen R. M., Montgomery W. W., Dainty I. A., Dubuque L. K., Whiting R. L. The interaction of methoctramine and himbacine at atrial, smooth muscle and endothelial muscarinic receptors in vitro. Br J Pharmacol. 1988 Dec;95(4):1031–1038. doi: 10.1111/j.1476-5381.1988.tb11736.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hammer R., Berrie C. P., Birdsall N. J., Burgen A. S., Hulme E. C. Pirenzepine distinguishes between different subclasses of muscarinic receptors. Nature. 1980 Jan 3;283(5742):90–92. doi: 10.1038/283090a0. [DOI] [PubMed] [Google Scholar]
  18. Hammer R., Giraldo E., Schiavi G. B., Monferini E., Ladinsky H. Binding profile of a novel cardioselective muscarine receptor antagonist, AF-DX 116, to membranes of peripheral tissues and brain in the rat. Life Sci. 1986 May 5;38(18):1653–1662. doi: 10.1016/0024-3205(86)90409-1. [DOI] [PubMed] [Google Scholar]
  19. Hulme E. C., Birdsall N. J., Buckley N. J. Muscarinic receptor subtypes. Annu Rev Pharmacol Toxicol. 1990;30:633–673. doi: 10.1146/annurev.pa.30.040190.003221. [DOI] [PubMed] [Google Scholar]
  20. Irie K., Furukawa K., Nomoto T., Fujii E., Muraki T. Developmental changes in the response of rat isolated duodenum to nicotine. Eur J Pharmacol. 1994 Jan 4;251(1):75–81. doi: 10.1016/0014-2999(94)90445-6. [DOI] [PubMed] [Google Scholar]
  21. Kenakin T. P., Beek D. The effects on Schild regressions of antagonist removal from the receptor compartment by a saturable process. Naunyn Schmiedebergs Arch Pharmacol. 1987 Feb;335(2):103–108. doi: 10.1007/BF00177709. [DOI] [PubMed] [Google Scholar]
  22. Lambrecht G., Feifel R., Forth B., Strohmann C., Tacke R., Mutschler E. p-fluoro-hexahydro-sila-difenidol: the first M2 beta-selective muscarinic antagonist. Eur J Pharmacol. 1988 Jul 26;152(1-2):193–194. doi: 10.1016/0014-2999(88)90856-4. [DOI] [PubMed] [Google Scholar]
  23. Lazareno S., Buckley N. J., Roberts F. F. Characterization of muscarinic M4 binding sites in rabbit lung, chicken heart, and NG108-15 cells. Mol Pharmacol. 1990 Dec;38(6):805–815. [PubMed] [Google Scholar]
  24. MUSKUS A. J. Effect of pretreatment with reserpine and reserpine analogs on the response of isolated guinea-pig atria to tyramine. J Pharmacol Exp Ther. 1962 Dec;138:296–300. [PubMed] [Google Scholar]
  25. Maggio R., Barbier P., Bolognesi M. L., Minarini A., Tedeschi D., Melchiorre C. Binding profile of the selective muscarinic receptor antagonist tripitramine. Eur J Pharmacol. 1994 Aug 16;268(3):459–462. doi: 10.1016/0922-4106(94)90075-2. [DOI] [PubMed] [Google Scholar]
  26. McKinney M., Coyle J. T. The potential for muscarinic receptor subtype-specific pharmacotherapy for Alzheimer's disease. Mayo Clin Proc. 1991 Dec;66(12):1225–1237. doi: 10.1016/s0025-6196(12)62474-4. [DOI] [PubMed] [Google Scholar]
  27. Melchiorre C., Angeli P., Lambrecht G., Mutschler E., Picchio M. T., Wess J. Antimuscarinic action of methoctramine, a new cardioselective M-2 muscarinic receptor antagonist, alone and in combination with atropine and gallamine. Eur J Pharmacol. 1987 Dec 1;144(2):117–124. doi: 10.1016/0014-2999(87)90509-7. [DOI] [PubMed] [Google Scholar]
  28. Melchiorre C., Bolognesi M. L., Chiarini A., Minarini A., Spampinato S. Synthesis and biological activity of some methoctramine-related tetraamines bearing a 11-acetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one moiety as antimuscarinics: a second generation of highly selective M2 muscarinic receptor antagonists. J Med Chem. 1993 Nov 12;36(23):3734–3737. doi: 10.1021/jm00075a032. [DOI] [PubMed] [Google Scholar]
  29. Melchiorre C., Cassinelli A., Quaglia W. Differential blockade of muscarinic receptor subtypes by polymethylene tetraamines. Novel class of selective antagonists of cardiac M-2 muscarinic receptors. J Med Chem. 1987 Jan;30(1):201–204. doi: 10.1021/jm00384a034. [DOI] [PubMed] [Google Scholar]
  30. Melchiorre C. Polymethylene tetraamines: a novel class of cardioselective M2-antagonists. Med Res Rev. 1990 Jul-Sep;10(3):327–349. doi: 10.1002/med.2610100303. [DOI] [PubMed] [Google Scholar]
  31. Melchiorre C. Polymethylene tetramines: a new generation of selective muscarinic antagonists. Trends Pharmacol Sci. 1988 Jun;9(6):216–220. doi: 10.1016/0165-6147(88)90089-2. [DOI] [PubMed] [Google Scholar]
  32. Melchiorre C., Quaglia W., Picchio M. T., Giardinà D., Brasili L., Angeli P. Structure-activity relationships among methoctramine-related polymethylene tetraamines. Chain-length and substituent effects on M-2 muscarinic receptor blocking activity. J Med Chem. 1989 Jan;32(1):79–84. doi: 10.1021/jm00121a017. [DOI] [PubMed] [Google Scholar]
  33. Michel A. D., Delmendo R., Stefanich E., Whiting R. L. Binding characteristics of the muscarinic receptor subtype of the NG108-15 cell line. Naunyn Schmiedebergs Arch Pharmacol. 1989 Jul;340(1):62–67. doi: 10.1007/BF00169208. [DOI] [PubMed] [Google Scholar]
  34. PATON W. D., RANG H. P. THE UPTAKE OF ATROPINE AND RELATED DRUGS BY INTESTINAL SMOOTH MUSCLE OF THE GUINEA-PIG IN RELATION TO ACETYLCHOLINE RECEPTORS. Proc R Soc Lond B Biol Sci. 1965 Aug 24;163:1–44. doi: 10.1098/rspb.1965.0058. [DOI] [PubMed] [Google Scholar]
  35. Roffel A. F., Elzinga C. R., Zaagsma J. Cholinergic contraction of the guinea pig lung strip is mediated by muscarinic M2-like receptors. Eur J Pharmacol. 1993 Dec 7;250(2):267–279. doi: 10.1016/0014-2999(93)90391-t. [DOI] [PubMed] [Google Scholar]
  36. Stockton J. M., Birdsall N. J., Burgen A. S., Hulme E. C. Modification of the binding properties of muscarinic receptors by gallamine. Mol Pharmacol. 1983 May;23(3):551–557. [PubMed] [Google Scholar]
  37. Tallarida R. J., Cowan A., Adler M. W. pA2 and receptor differentiation: a statistical analysis of competitive antagonism. Life Sci. 1979 Aug 20;25(8):637–654. doi: 10.1016/0024-3205(79)90505-8. [DOI] [PubMed] [Google Scholar]
  38. Temma K., Akera T., Brody T. M. Hydroxylated chlorpromazine metabolites: positive inotropic action and the release of catecholamines. Mol Pharmacol. 1977 Nov;13(6):1076–1085. [PubMed] [Google Scholar]
  39. VAN ROSSUM J. M. Cumulative dose-response curves. II. Technique for the making of dose-response curves in isolated organs and the evaluation of drug parameters. Arch Int Pharmacodyn Ther. 1963;143:299–330. [PubMed] [Google Scholar]
  40. Waelbroeck M., Camus J., Tastenoy M., Mutschler E., Strohmann C., Tacke R., Lambrecht G., Christophe J. Binding affinities of hexahydro-difenidol and hexahydro-sila-difenidol analogues at four muscarinic receptor subtypes: constitutional and stereochemical aspects. Eur J Pharmacol. 1991 Feb 25;206(2):95–103. doi: 10.1016/0922-4106(91)90017-c. [DOI] [PubMed] [Google Scholar]
  41. Watson N., Barnes P. J., Maclagan J. Actions of methoctramine, a muscarinic M2 receptor antagonist, on muscarinic and nicotinic cholinoceptors in guinea-pig airways in vivo and in vitro. Br J Pharmacol. 1992 Jan;105(1):107–112. doi: 10.1111/j.1476-5381.1992.tb14219.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Wess J. Molecular basis of muscarinic acetylcholine receptor function. Trends Pharmacol Sci. 1993 Aug;14(8):308–313. doi: 10.1016/0165-6147(93)90049-p. [DOI] [PubMed] [Google Scholar]

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