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. 1995 Nov;116(5):2385–2390. doi: 10.1111/j.1476-5381.1995.tb15084.x

The in vivo pharmacological profile of a 5-HT1 receptor agonist, CP-122,288, a selective inhibitor of neurogenic inflammation.

P Gupta 1, D Brown 1, P Butler 1, P Ellis 1, K L Grayson 1, G C Land 1, J E Macor 1, S F Robson 1, M J Wythes 1, N B Shepperson 1
PMCID: PMC1909056  PMID: 8581273

Abstract

1. The aim of the present study was to investigate the in vivo pharmacological profile of CP-122,288, an indole-derivative with a conformationally restricted N-methylpyrrolidinyl basic side chain in the C-3 position. This C-3 substituent structurally differentiates CP-122,288 from the 5-HT1D receptor agonist sumatriptan, which possesses an N,N-dimethylaminoethyl group. [Formula: see text] 2. When administered prior to electrical stimulation of the trigeminal ganglion, CP-122,288 (0.3-300 ng kg-1, i.v.) produced a dose-related inhibition of plasma protein extravasation in rat dura mater (minimum effective dose, MED, 3 ng kg-1 i.v., P < 0.05; maximal inhibition of plasma extravasation at 30 ng kg-1 i.v., P < 0.01). Sumatriptan produced a similar inhibition of plasma leakage in the dura, but at much higher dose levels (MED, 100 micrograms kg-1 i.v., P < 0.05). Thus, CP-122,288 is of the order of 10(4) fold more potent than sumatriptan. 3. At all doses tested, CP-122,288 did not inhibit plasma protein extravasation measured in extracranial tissues such as the lower lip, eyelid, and conjunctiva. 4. In a separate series of studies in the anaesthetized rat, CP-122,288 (0.003-3 micrograms kg-1 i.v.) produced no change in either heart rate or mean arterial blood pressure, thus demonstrating that doses of CP-122,288 which inhibit plasma protein leakage in rat dura, are devoid of hemodynamic effects. 5. Following a 5 min period of electrical stimulation of the trigeminal ganglion, a 20 min period of sustained neurogenically-driven plasma extravasation, occurring in the absence of electrical stimulation, was initiated. By administration of the compound 5 min after completing the phase of electrical stimulation, this protocol permitted the evaluation of the activity of CP-122,288 on an ongoing and established inflammatory event. CP-122,288 (30 and 300 ng kg-1, i.v., P < 0.01 and P < 0.05, respectively) produced a complete inhibition of plasma protein leakage which was consistent with its effects when administered prior to trigeminal ganglion stimulation. 6. In the anaesthetized dog, CP-122,288 and sumatriptan, at 1-300 micrograms kg-1, i.v., produced a dose-dependent reduction in carotid arterial blood flow and coronary arterial diameter. These data demonstrate that sumatriptan inhibits neurogenic inflammation in the rat (MED, 100 micrograms kg-1, i.v.), and produces vasoconstriction in the dog, over a similar dose-range. Interestingly, doses of CP-122,288 that inhibit neurogenic inflammation in rat dura mater (0.3-300 ng kg-1) were demonstrated to be devoid of vasoconstrictor activity in either the carotid or coronary vascular beds of dog. 7. These data demonstrate that in the rat, CP-122,288 is a highly potent and selective inhibitor of neurogenic inflammation in intracranial tissues, at doses which are devoid of vasoconstrictor activity in dog. Potentially, CP-122,288 may be of use for the acute treatment of migraine, without the risk of cardiovascular side-effects.

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Selected References

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  1. Bax W. A., Van Heuven-Nolsen D., Bos E., Simoons M. L., Saxena P. R. 5-Hydroxytryptamine-induced contractions of the human isolated saphenous vein: involvement of 5-HT2 and 5-HT1D-like receptors, and a comparison with grafted veins. Naunyn Schmiedebergs Arch Pharmacol. 1992 May;345(5):500–508. doi: 10.1007/BF00168940. [DOI] [PubMed] [Google Scholar]
  2. Buzzi M. G., Moskowitz M. A., Peroutka S. J., Byun B. Further characterization of the putative 5-HT receptor which mediates blockade of neurogenic plasma extravasation in rat dura mater. Br J Pharmacol. 1991 Jun;103(2):1421–1428. doi: 10.1111/j.1476-5381.1991.tb09805.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cocks T. M., Kemp B. K., Pruneau D., Angus J. A. Comparison of contractile responses to 5-hydroxytryptamine and sumatriptan in human isolated coronary artery: synergy with the thromboxane A2-receptor agonist, U46619. Br J Pharmacol. 1993 Sep;110(1):360–368. doi: 10.1111/j.1476-5381.1993.tb13818.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Connor H. E., Feniuk W., Humphrey P. P. 5-Hydroxytryptamine contracts human coronary arteries predominantly via 5-HT2 receptor activation. Eur J Pharmacol. 1989 Feb 14;161(1):91–94. doi: 10.1016/0014-2999(89)90184-2. [DOI] [PubMed] [Google Scholar]
  5. Cutrer F. M., Schoenfeld D., Limmroth V., Panahian N., Moskowitz M. A. Suppression by the sumatriptan analogue, CP-122,288 of c-fos immunoreactivity in trigeminal nucleus caudalis induced by intracisternal capsaicin. Br J Pharmacol. 1995 Mar;114(5):987–992. doi: 10.1111/j.1476-5381.1995.tb13302.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. DeLean A., Munson P. J., Rodbard D. Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves. Am J Physiol. 1978 Aug;235(2):E97–102. doi: 10.1152/ajpendo.1978.235.2.E97. [DOI] [PubMed] [Google Scholar]
  7. Feniuk W., Humphrey P. P., Perren M. J. The selective carotid arterial vasoconstrictor action of GR43175 in anaesthetized dogs. Br J Pharmacol. 1989 Jan;96(1):83–90. doi: 10.1111/j.1476-5381.1989.tb11787.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Huang Z., Byun B., Matsubara T., Moskowitz M. A. Time-dependent blockade of neurogenic plasma extravasation in dura mater by 5-HT1B/D agonists and endopeptidase 24.11. Br J Pharmacol. 1993 Feb;108(2):331–335. doi: 10.1111/j.1476-5381.1993.tb12805.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Humphrey P. P., Feniuk W. Mode of action of the anti-migraine drug sumatriptan. Trends Pharmacol Sci. 1991 Dec;12(12):444–446. doi: 10.1016/0165-6147(91)90630-b. [DOI] [PubMed] [Google Scholar]
  10. Kajekar R., Gupta P., Shepperson N. B., Brain S. D. Effect of a 5-HT1 receptor agonist, CP-122,288, on oedema formation induced by stimulation of the rat saphenous nerve. Br J Pharmacol. 1995 May;115(1):1–2. doi: 10.1111/j.1476-5381.1995.tb16310.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kaumann A. J., Frenken M., Posival H., Brown A. M. Variable participation of 5-HT1-like receptors and 5-HT2 receptors in serotonin-induced contraction of human isolated coronary arteries. 5-HT1-like receptors resemble cloned 5-HT1D beta receptors. Circulation. 1994 Sep;90(3):1141–1153. doi: 10.1161/01.cir.90.3.1141. [DOI] [PubMed] [Google Scholar]
  12. Lee W. S., Moskowitz M. A. Conformationally restricted sumatriptan analogues, CP-122,288 and CP-122,638 exhibit enhanced potency against neurogenic inflammation in dura mater. Brain Res. 1993 Oct 29;626(1-2):303–305. doi: 10.1016/0006-8993(93)90591-a. [DOI] [PubMed] [Google Scholar]
  13. MacIntyre P. D., Bhargava B., Hogg K. J., Gemmill J. D., Hillis W. S. Effect of subcutaneous sumatriptan, a selective 5HT1 agonist, on the systemic, pulmonary, and coronary circulation. Circulation. 1993 Feb;87(2):401–405. doi: 10.1161/01.cir.87.2.401. [DOI] [PubMed] [Google Scholar]
  14. Moskowitz M. A. Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine. Trends Pharmacol Sci. 1992 Aug;13(8):307–311. doi: 10.1016/0165-6147(92)90097-p. [DOI] [PubMed] [Google Scholar]
  15. Ottervanger J. P., Paalman H. J., Boxma G. L., Stricker B. H. Transmural myocardial infarction with sumatriptan. Lancet. 1993 Apr 3;341(8849):861–862. doi: 10.1016/0140-6736(93)93064-8. [DOI] [PubMed] [Google Scholar]
  16. Parsons A. A., Stutchbury C., Raval P., Kaumann A. J. Sumatriptan contracts large coronary arteries of beagle dogs through 5-HT1-like receptors. Naunyn Schmiedebergs Arch Pharmacol. 1992 Nov;346(5):592–596. doi: 10.1007/BF00169018. [DOI] [PubMed] [Google Scholar]
  17. Rebeck G. W., Maynard K. I., Hyman B. T., Moskowitz M. A. Selective 5-HT1D alpha serotonin receptor gene expression in trigeminal ganglia: implications for antimigraine drug development. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3666–3669. doi: 10.1073/pnas.91.9.3666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Saito K., Markowitz S., Moskowitz M. A. Ergot alkaloids block neurogenic extravasation in dura mater: proposed action in vascular headaches. Ann Neurol. 1988 Dec;24(6):732–737. doi: 10.1002/ana.410240607. [DOI] [PubMed] [Google Scholar]
  19. Willett F., Curzen N., Adams J., Armitage M. Coronary vasospasm induced by subcutaneous sumatriptan. BMJ. 1992 May 30;304(6839):1415–1415. doi: 10.1136/bmj.304.6839.1415. [DOI] [PMC free article] [PubMed] [Google Scholar]

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