BGC20-1531, a novel, potent and selective prostanoid EP receptor antagonist: a putative new treatment for migraine headache.

BACKGROUND AND PURPOSE: Prostanoid EP(4) receptor antagonists may have therapeutic utility in the treatment of migraine since EP(4) receptors have been shown to be involved in prostaglandin (PG)E(2)-induced cerebral vascular dilatation, which may be an important contributor to migraine pain. This study reports the pharmacological characterization of BGC20-1531, a novel EP(4) receptor antagonist. EXPERIMENTAL APPROACH: BGC20-1531 was characterized in radioligand binding and in vitro functional assays employing recombinant and native EP(4) receptors. Changes in canine carotid haemodynamics were used to assess the pharmacodynamic profile of BGC20-1531 in vivo. KEY RESULTS: BGC20-1531 exhibited high affinity at recombinant human EP(4) receptors expressed in cell lines (pK(B) 7.6) and native EP(4) receptors in human cerebral and meningeal artery (pK(B) 7.6-7.8) but showed no appreciable affinity at a wide range of other receptors (including other prostanoid receptors), channels, transporters and enzymes (pKi < 5). BGC20-1531 competitively antagonized PGE(2)-induced vasodilatation of human middle cerebral (pK(B) 7.8) and meningeal (pK(B) 7.6) arteries in vitro, but had no effect on responses induced by PGE(2) on coronary, pulmonary or renal arteries in vitro. BGC20-1531 (1-10 mg.kg(-1) i.v.) caused a dose-dependent antagonism of the PGE(2)-induced increase in canine carotid blood flow in vivo. CONCLUSIONS AND IMPLICATIONS: BGC20-1531 is a potent and selective antagonist at EP(4) receptors in vitro and in vivo, with the potential to alleviate the symptoms of migraine that result from cerebral vasodilatation. BGC20-1531 is currently in clinical development for the treatment of migraine headache.

Naratriptan: biological profile in animal models relevant to migraine.

The biological profile of naratriptan (N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethane-sulphonamide), a novel 5HT1B/1D receptor agonist, was investigated in a variety of experimental models of relevance to migraine. Naratriptan has high affinity for human recombinant 5HT1B and 5HT1D receptors (pKi = 8.7 +/- 0.03 and 8.3 +/- 0.1, respectively) and causes contractions of dog isolated basilar and middle cerebral artery (EC50 values of 0.11 and 0.07 microM, respectively). Naratriptan causes small contractions of human isolated coronary arteries (EC50 value of 0.17 microM; maximum contraction equivalent to 33% of 5HT maximum). In anaesthetized dogs, naratriptan causes selective vasoconstriction of the carotid arterial bed (CD50 dose = 19 +/- 3 micrograms kg-1) and, in anaesthetized rats, naratriptan selectively inhibits neurogenic plasma protein extravasation in the dura (ID50 = 4.1 micrograms kg-1). In a variety of antinociceptive tests, naratriptan has no effect even at high doses. In conscious rats and dogs, naratriptan has high oral bioavailability (71% and 95%, respectively). The data show that naratriptan is a selective agonist at 5HT1B/1D receptors, with a pharmacological profile very similar to that of sumatriptan, albeit 2-3 fold more potent. These observations, coupled with high oral bioavailability in animals, suggest that naratriptan has the profile of an orally effective anti-migraine drug.

GR113808: a novel, selective antagonist with high affinity at the 5-HT4 receptor.

1. The 5-HT4 receptor has only recently been identified but has yet to be cloned. This paper describes the pharmacology of a potent and selective 5-HT4 receptor antagonist, GR113808, which will be useful in the further characterization of this receptor. 2. On the guinea-pig ascending colon, GR113808 (1 nM-0.1 microM) behaved as an antagonist of 5-hydroxytryptamine (5-HT)-induced contraction, producing rightward displacements of the concentration-effect curve to 5-HT and a concentration-related depression of the maximum effect. However, the compound had no effect on cholecystokinin (CCK-8)-induced contraction in concentrations up to 1 microM. 3. In the guinea-pig colon preparation, onset and offset of the antagonism by GR113808 of 5-HT-induced contraction was examined. Incubation of the tissues for either 15 min, 30 min or 60 min produced similar rightward displacements of the concentration-effect curves to 5-HT, with no increase in the degree of depression of the maxima with increasing time of incubation. Experiments examining offset of antagonism (0.01 microM) demonstrated that washout for 30 min was required to reverse fully the effects of the antagonist. 4. Potency estimates in the colon for GR113808 were made by determining approximate pA2 values (30 min) using the Gaddum equation. The values obtained were 9.2, 9.7 and 9.2 when tested against the agonists 5-HT, 5-methoxytryptamine and R,S-zacopride respectively. 5. On the carbachol-contracted tunica muscularis mucosae preparation of the rat thoracic oesophagus, GR113808 behaved as an antagonist of 5-HT-induced relaxation, producing no reduction in maximum response. Analysis of these data yielded a pA2 of 9.3. GR1 13808 also antagonised the relaxant effects of 5-methoxytryptamine (pA2 = 9.0) and R,S-zacopride (pA2 = 9.4). The compound had no effect on isoprenaline-induced relaxation of the carbachol-contracted oesophagus at a concentration of 1 MicroM.6. In tests of selectivity, GR113808 had only low affinity for 5-HT3 receptors (pKi = 6.0) and had no functional activity at either 5-HT2 or 5-HT1-like receptors on vascular smooth muscle preparations. In a range of binding assays, GRi 13808 was shown to have no appreciable affinity for any other receptor type investigated.7. In the anaesthetized piglet, GRI13808 was a potent antagonist of 5-methoxytryptamine-induced tachycardia (mean DRo = 97.2 microg kg-1 h-1). The compound was ineffective against isoprenaline-induced tachycardia.8. The present results are discussed in comparison with those for existing antagonists at the 5-HT4receptor. The results of this study indicate that GRI13808 will be a valuable antagonist for studying 5-HT4 receptor mechanisms in vitro and in vivo and validate its use as a radioligand for determining 5-HT4 receptor distribution.

1-(m-chlorophenyl)-biguanide, a potent high affinity 5-HT3 receptor agonist.

1-(m-Chlorophenyl)-biguanide (mCPBG) was examined and compared with three 5-HT3 receptor agonists in three 5-HT3 receptor models. mCPBG inhibited [3H]GR67330 binding to 5-HT3 receptors with high affinity (IC50 1.5 nM). mCPBG depolarized the rat vagus nerve with an EC50 one tenth of that for 5-HT (0.05 vs. 0.46 microM); the maximum depolarization was approximately half that for 5-HT. The mCPBG depolarization was potently blocked by the selective 5-HT3 antagonist, ondansetron (pKB 8.6 +/- 0.1). In anaesthetised cats, mCPBG potently evoked the Bezold-Jarisch reflex which was blocked by low doses of ondansetron (10 micrograms/kg i.v.). It is concluded that mCPBG is a potent, high affinity 5-HT3 receptor agonist.

The pharmacology of the novel 5-HT1-like receptor agonist, GR43175.

We describe the identification of a novel drug, GR43175, for the acute treatment of migraine. GR43175 is a tryptamine analogue with a very selective agonist action at a 5-HT1-like receptor subtype first identified in the dog saphenous vein. Using this drug as a research probe, we have now shown that this 5-HT receptor type predominates in the carotid circulation, which explains the remarkably selective vasoconstrictor action of GR43175 in vivo in the carotid arterial bed of dogs and cats. Its vasoconstrictor action can be shown to be localized even further to arteriovenous anastomoses (shunts) within the carotid circulation, in such a way that blood flow to the brain as well as to extracerebral capillary beds remains unaffected or may even be increased. In the treatment of migraine demonstrated to date, the impressive effectiveness of GR43175 must reinforce the evidence in favour of an important vascular component being involved in the aetiology of the disease. The question is again raised as to whether the opening of carotid shunts is involved, as suggested by Heyck. If not, an alternative vascular locus needs to be identified.

GR43175, a selective agonist for the 5-HT1-like receptor in dog isolated saphenous vein.

1. We describe the actions of a novel and selective 5-HT1-like receptor agonist, GR43175, in a range of isolated tissue preparations containing different 5-hydroxytryptamine (5-HT) receptor types. 2. GR43175 was a potent agonist at 5-HT1-like receptors mediating contraction of the dog isolated saphenous vein and also at those inhibiting neuronally mediated contractions in the same preparations. For both actions, GR43175 was approximately four times weaker than 5-HT. 3. GR43175 was devoid of agonist properties at 5-HT1-like receptors mediating relaxation of the cat isolated saphenous vein. 4. GR43175 was devoid of agonist properties at 5-HT2 receptors mediating contraction of the rabbit isolated aorta, pig coronary artery, greyhound coronary artery and beagle femoral artery. 5. GR43175 was devoid of agonist properties at 5-HT3 receptors mediating depolarization of the rat isolated vagus nerve. 6. The contractile response to GR43175 in the dog isolated saphenous vein was selectively antagonized by methiothepin but was resistant to antagonism by the 5-HT2 receptor blocking drug ketanserin and the 5-HT3 receptor blocking drug MDL 72222. Methiothepin antagonized the contractile action of 5-HT and GR43175 to an equal extent suggesting that both agonists act at the same receptor. 7. The results demonstrate that GR43175 is a highly selective agonist for the 5-HT1-like receptors found in the dog saphenous vein. The absence of an action of GR43175 at 5-HT1-like receptors mediating relaxation of the cat isolated saphenous vein provides further evidence that 5-HT1-like receptors are heterogeneous.