No abstract

Migraine has long been considered as a "vascular headache" but clearly neurological mechanisms are involved. The pathophysiology appears to somehow involve serotonin, both peripherally and centrally, but its involvement may be just epiphenomenal. Adding to the enigma it is apparent that many of the presently available drugs for the treatment of migraine interact in one way or another with serotonin receptors. However, they tend to have a number of other unrelated actions and they are only of limited clinical value. Interestingly a promising new drug for the treatment of the acute attack, sumatriptan, has a very selective action as an agonist at a specific 5-HT1-like receptor sub-type, mediating vasoconstriction, which is localized on cranial blood vessels. Its action may, or may not, be independent of any involvement of serotonin in the genesis of migraine. Hopefully though, current attempts to determine sumatriptan's mechanism of action will shed further light on the pathology of migraine itself and the putative involvement of serotonin.

1 Using recently available selective agonists and antagonists we have examined further our postulate (Apperley et al., 1980) that 5-hydroxytryptamine (5-HT) mediates contraction of dog saphenous vein via a different 5-HT receptor type from that in the rabbit aorta. 2 In the rabbit isolated aorta, ketanserin and spiperone were potent, specific, competitively-acting antagonists of the contractile effects of 5-HT. 3 In contrast, in the dog isolated saphenous vein neither ketanserin nor spiperone caused any rightward displacement of concentration-response curves to 5-HT although the maximum response was reduced by about 10%. 4 In the rabbit aorta 5-carboxamidotryptamine (5-CONH2-T) was a weak agonist whilst the 5-N,Ndimethyl and 5-N-ethyl derivatives were even weaker or inactive. The contractile effect of 5-CONH2-T in the rabbit aorta was potently and competitively antagonized by ketanserin. 5 In contrast, in the dog saphenous vein 5-CONH2-T and its 5-N,N-dimethyl and 5-N-ethyl derivatives were all potent agonists. The contractile effect of 5-CONH2-T was not markedly affected by ketanserin. 6 The profile of action of ketanserin and spiperone in the rabbit aorta is consistent with the view that 5-HT2 receptors mediate contraction in this preparation. However, the 5-HT receptor mediating contraction in the dog saphenous vein appears to be '5-HT1-like', sharing a number of characteristics with the 5-HT, recognition site identified from [3H]-5-HT ligand binding studies in brain tissue.

1 GR43175 is a highly selective agonist at 5-HTI-like receptors in the dog saphenous vein. This study describes the haemodynamic effects of GR43175 in barbitone-anaesthetized dogs. 2 GR43175 (1-lOOOpgkg-1, i.v.) produced dose-dependent decreases in carotid arterial blood flow with little or no change in arterial blood pressure. The decrease in blood flow was associated with an increase in carotid arterial vascular resistance. In preliminary studies, the dose of GR43175 producing 50% of the maximum carotid vasoconstrictor response was 39 + 8 jig kg-1, i.v. 3 In comparative regional haemodynamic studies, GR43175 (1-1000igkg-', i.v.) had little effect on total peripheral resistance or resistance in the mesenteric, vertebral and coronary arterial vascular beds. Low doses of GR43175 decreased, whilst high doses (100 pg kg-1, i.v. and above) increased femoral arterial vascular resistance. GR43175 (1-lOOOpgkg-1, i.v.) had no effect on respiratory inflation pressure. In doses of lOOpgkg-1 i.v. and above, GR43175 caused small decreases in heart rate.4 The carotid arterial vasoconstrictor action of GR43175 was resistant to antagonism by the 5-HT2 receptor, 5-HT3 receptor and x-adrenoceptor blocking drugs, ketanserin, MDL72222 and phentolamine respectively, but could be antagonized by the non-selective 5-HT1-like receptor blocking drug methiothepin. Methiothepin had no effect on the carotid vasoconstrictor action of the thromboxane A2 mimetic, U46619. 5 The results demonstrate that GR43175 produces a selective vasoconstriction in the carotid arterial circulation of anaesthetized dogs via activation of 5-HT,-like receptors, which appear similar to those mediating contraction of the dog isolated saphenous vein.

A short stereoselective synthesis of a series of chiral 7-aryl-2,5-diketopiperazines oxytocin antagonists is described. Varying the functionality and substitution pattern of substituents in the 7-aryl ring and varying the chirality of this exocyclic ring have produced potent oxytocin antagonists (pK(i) > 8.5). SAR and pharmacokinetic profiling of this series of (3R,6R,7R)-2,5-diketopiperazines together with the introduction of an ortho F group in the 7-aryl ring to improve rat pK has culminated in the 2',4'-difluorophenyldiketopiperazine derivative 37, a highly potent oxytocin antagonist against the human oxytocin receptor (pK(i) = 8.9) that has >1000-fold selectivity over all three vasopressin receptors V1a, V2, and V1b. It has good bioavailability (46%) in the rat and moderate bioavailability (13-31%) in the dog and is more active in vivo in the rat than atosiban (rat DR(10) = 0.44 mg/kg iv).