It is evident that in the last decade or so, a vast amount of new information has become available concerning the various 5-HT receptor types and their characteristics. This derives from two main research approaches, operational pharmacology, using selective ligands (both agonists and antagonists), and, more recently, molecular biology. Although the scientific community continues to deliberate about the hierarchy of criteria for neurotransmitter receptor characterisation, there seems good agreement between the two approaches regarding 5-HT receptor classification. In addition, the information regarding transduction mechanisms and second messengers is also entirely consistent. Thus, on the basis of these essential criteria for receptor characterisation and classification, there are at least three main groups or classes of 5-HT receptor: 5-HT1, 5-HT2, and 5-HT3. Each group is not only operationally but also structurally distinct, with each receptor group having its own distinct transducing system. The more recently identified 5-HT4 receptor almost undoubtedly represents a fourth 5-HT receptor class on the basis of operational and transductional data, but this will only be definitively shown when the cDNA for the receptor has been cloned and the amino acid sequence of the protein is known. Although those 5-HT receptors that have been fully characterised and classified to date (and, hence, named with confidence) would seem to mediate the majority of the actions of 5-HT throughout the mammalian body, not all receptors for 5-HT are fully encompassed within our scheme of classification. These apparent anomalies must be recognised and need further study. They may or may not represent new groups of 5-HT receptor or subtypes of already known groups of 5-HT receptor. Even though the cDNAs for the 5-ht1E, 5-ht1F, 5-ht5, 5-ht6, and 5-ht7 receptors have been cloned and their amino acid sequence defined, more data are necessary concerning their operational and transductional characteristics before one can be confident of the suitability of their appellations. Therefore, it is important to rationalise in concert all of the available data from studies involving both operational approaches of the classical pharmacological type and those from molecular and cellular biology.(ABSTRACT TRUNCATED AT 400 WORDS)

International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin).

1. This paper describes the pharmacology of the novel 5-hydroxytryptamine3 (5-HT3) receptor antagonist GR38032F. 2. On the isolated vagus nerve and superior cervical ganglion of the rat, R,S-GR38032F behaved as a reversible competitive antagonist of 5-HT-induced depolarization with pKB values of 8.61 +/- 0.08 (n = 19) and 8.13 +/- 0.07 (n = 16), respectively. The resolved R- and S-isomers of GR38032F were approximately equipotent as 5-HT antagonists on the rat vagus nerve: the pKB values were 8.95 +/- 0.05 (n = 16) and 8.63 +/- 0.08 (n = 17), respectively. R,S-GR38032F was also an effective antagonist of 5-HT on the rabbit isolated vagus nerve: in this case the pKB value was 9.40 +/- 0.14 (n = 4). 3. On the rabbit isolated heart, low concentrations of R,S-GR38032F (3 X 10(-11)-1 X 10(-9) M) antagonized the positive chronotropic effect of 5-HT and 2-methyl-5-hydroxytryptamine (2-methyl-5-HT). However, the effects of the compound did not appear consistent with simple reversible competition. 4. On the longitudinal smooth muscle of the guinea-pig ileum, R,S-GR38032F caused concentration-dependent parallel rightward displacement of the 2-methyl-5-HT concentration-contraction response curve; in contrast, a portion of the response to 5-HT appeared resistant to R,S-GR38032F. pKB values estimated from the effects of the compound against 2-methyl-5-HT or the inhibitable portion of the response to 5-HT were 7.31 +/- 0.06 (n = 8) and 7.33 +/- 0.13 (n = 8), respectively. Against 2-methyl-5-HT, R-GR38032F seemed more potent (pKB 7.20 +/- 0.10; n = 6) than S-GR38032F (pKB 6.30 +/- 0.05; n = 6). 5. R,S-GR38032F is highly selective for 5-HT3 receptors, and at concentrations of 3 X 10(-6)-3 X 10(-5) M, had negligible agonist or antagonist activity on other 5-HT or non-5-HT receptor-containing tissues on which it was tested. 6. The potency and duration of action of R,S-GR38032F in blocking 5-HT3 receptors in vivo were assessed by measuring its ability to antagonize the bradycardic response to 5-HT or 2-methyl-5-HT administered intravenously (i.v.) to anaesthetized animals. For i.v. administration to the rat, the ED50 for R,S-GR38032F against 2-methyl-5-HT (100pgkg-1) was 0.4 (95% confidence limits 0.18- 0.87) ygkg-1 (n = 10); the corresponding value for oral administration to this species was 7.0 (3.0- 22.0)pgkg-' (n = 8-10 per dose level). R,S-GR38032F was similarly effective in the anaesthetized cat. 7. The present results are discussed with reference to the postulated existence of subtypes of the 5-HT3 receptor.

/pdf/pharmacological-properties-of-gr38032f-a-novel-antagonist-at-4rik2q2p9n.pdf

Pharmacological properties of GR38032F, a novel antagonist at 5-HT3 receptors

1 The actions of the prostaglandin H2 (PGH2) analogue, U-46619, have been compared with those of PGH2 on thromboxane A2 (TxA2) on a range of isolated smooth muscle preparations in a superfusion cascade system. 2 U-46619 was a potent agonist on guinea-pig lung strip, dog saphenous vein and rat and rabbit aortae. In contrast, U-46619 was weak or inactive on guinea-pig ileum and fundic strip, cat trachea and dog and cat iris sphincter muscles, preparations on which either PGE2 or PGF2 alpha was the most potent agonist studied. 3 PGH2 was active on all of the preparations and displayed little selectivity. On some of the preparations, the actions of PGH2 may have been mediated indirectly by conversion to other prostanoids. 4 In contrast, TxA2 displayed the same pattern of selectivity as U-46619, being a potent agonist on the lung strip and vascular preparations but weak or inactive on the others. 5 It is suggested that U-46619 is a selective TxA2-mimetic and that it should therefore be a valuable tool in the study of the actions of TxA2.

Comparison of the actions of U-46619, a prostaglandin H2-analogue, with those of prostaglandin H2 and thromboxane A2 on some isolated smooth muscle preparations

Studies of the characterisation of prostanoid receptors: A proposed classification

Patients with coronary vasospasm appear to be supersensitive to the coronary constrictor effects of ergonovine. To determine whether atherosclerosis alters arterial reactivity and sensitizes arteries to ergonovine, contractile responses of isolated aortae from control rabbits and from rabbits fed a high-cholesterol diet were compared. Aortic strips were mounted in a myograph for the monitoring of isometric tension, equilibrated in oxygenated Krebs buffer, and exposed to graded concentrations of agonists and antagonists. The concentration-response relation for ergonovine in atherosclerotic arteries exhibited a markedly depressed constrictor threshold concentration (0.5 pM vs. 0.23 muM in controls), a significantly lowered one-half effective dose (ED(50)) value, and an augmented maximal response. Furthermore, atherosclerotic arteries showed similar, although less pronounced changes in the concentration-response relation for serotonin. In contrast, responses to 34 mM KCl were virtually identical, and the concentration-response relation for phenylephrine were similar in the two groups. In control arteries, 0.1 muM phentolamine and 0.1 muM prazosin suppressed responses to 1 muM ergonovine by 71 and 90%, respectively. However, in atherosclerotic arteries alpha-blockers in the same concentration inhibited responses to 0.01 muM ergonovine by less than 10%. On the other hand, 0.1 muM cyproheptadine, a serotonergic antagonist, suppressed these responses by 82%. Thus, the supersensitivity to ergonovine appeared to be mediated predominantly by a serotonergic mechanism. These results indicate that smooth muscle in atherosclerotic arteries may be supersensitive to specific vasoconstricting stimuli, a change that might contribute to arterial dysfunction in vivo.

/pdf/supersensitivity-of-atherosclerotic-rabbit-aorta-to-3v2lwqangc.pdf

Supersensitivity of Atherosclerotic Rabbit Aorta to Ergonovine: MEDIATION BY A SEROTONERGIC MECHANISM

5-Hydroxytryptamine (5-HT) is thought to be implicated in the vascular disturbances of the external carotid artery bed associated with migraine. As part of a study of the pharmacology of some 5-HT antagonists used in the treatment of migraine we have examined the interactions of these drugs with 5-HT and noradrenaline in rabbit isolated ear artery and aortic strip. The results provide new information on the distribution of 5-HT-receptors in these preparations. In the aorta, 5-HT and noradrenaline were of similar potency in producing contractions. Methysergide produced very small contractions and was about 1000 times less potent than the other two agonists. In the ear artery noradrenaline produced monophasic vasoconstrictor responses, whereas 5-HT and methysergide produced prolonged biphasic responses. 5-HT was about 700 times less potent and methysergide about 4500 times less potent than noradrenaline. Methysergide was a better agonist in the ear artery than in the aorta. Biphasic responses to 5-HT and methysergide were also obtained in ear arteries from reserpine-treated rabbits indicating that neither agonist was acting by releasing endogenous noradrenaline. Pizotifen, cyproheptadine and phentolamine had no agonistic actions in either the aorta or ear artery. In the aorta methysergide, pizotifen and cyproheptadine were potent antagonists of 5-HT and much weaker antagonists of noradrenaline. Phentolamine possessed the opposite profile of selectivity. These results show that there are distinct receptors for 5-HT and noradrenaline in rabbit aorta. In the ear artery the pA2 values for each of the four antagonists were virtually identical against 5-HT and noradrenaline and similar to those obtained on alpha-adrenoceptors in the aorta. We conclude that 5-HT and noradrenaline act directly at alpha-receptors to produce vasoconstriction in the ear artery and that this preparation does not contain specific 5-HT receptors. This insight into the distribution of 5-HT receptors and alpha-receptors allows interpretation of the various actions of methysergide. In the aorta, methysergide was a potent antagonist at 5-HT-receptors and a weak partial agonist at alpha-receptors. In the ear artery, methysergide was a partial agonist at alpha-receptors; it was only a weak antagonist of 5-HT because this preparation does not contain specific 5-HT-receptors. The cross-reactivity demonstrated throughout these experiments indicates that 5-HT-receptors and alpha-receptors, although distinct entities, have features in common. These results are discussed in relation to the mode of action of methysergide, pizotifen and cyproheptadine in the treatment of migraine.

Receptors for 5-hydroxytryptamine and noradrenaline in rabbit isolated ear artery and aorta.

1 As part of an investigation into the mode of action of anti-migraine drugs, a study of the excitatory receptors for 5-hydroxytryptamine (5-HT) has been carried out in a range of isolated vascular preparations from the dog.

2 5-HT contracted the dog isolated femoral artery and saphenous vein over the concentration-range 1.0 × 10-8 to 5.0 × 10-6 mol/l.

3 In the femoral artery methysergide and cyproheptadine were potent, competitive and specific antagonists of the contractile responses to 5-HT, with pA2 values of 8.52 and 8.55 respectively.

4 In the saphenous vein, methysergide was only a weak antagonist of 5-HT. In addition, it was an agonist over the concentration-range 5.0 × 10-8 to 1.0 × 10-5 mol/l. Cyproheptadine was a weak and unsurmountable antagonist of contractile responses to 5-HT and methysergide.

5 Contractile responses to 5-HT and methysergide in the saphenous vein were not antagonized by morphine (3.0 × 10-5 mol/l), indomethacin (5.0 × 10-5 mol/l), phentolamine (5.0 × 10-7 mol/l), propranolol (1.0 × 10-6 mol/l), atropine (1.0 × 10-6 mol/l), mepyramine (1.0 × 10-6 mol/l) or cimetidine (1.0 × 10-5 mol/l).

6 In the external carotid and lingual arteries the pattern of activity obtained with methysergide and cyproheptadine was the same as that in the femoral artery, while in the auricular artery the pattern of activity was the same as that in the saphenous vein.

7 The results are consistent with the hypothesis that there are two types of receptor mediating 5-HT-induced vasoconstriction in dog vasculature. One type, characterized by the pattern of activity obtained in the femoral artery, is like the previously described `D-receptor'. The other type, characterized by the pattern of activity obtained in the saphenous vein, has not been described before. The verification of this hypothesis requires the identification of a specific antagonist of 5-HT and methysergide in the saphenous vein.

Evidence for two types of excitatory receptor for 5-hydroxytryptamine in dog isolated vasculature

Two types of excitatory receptor for 5-hydroxytryptamine in dog vasculature? [proceedings].

Proceedings: Receptors for 5-hydroxytryptamine and noradrenaline in rabbit aorta and central ear artery.

Rabbit ear arteries were isolated and perfused at a constant flow rate so that the perfusate flowed into the fluid bathing the adventitial surface of the artery. Submaximal doses of intraluminally applied noradrenaline injected as a bolus into the perfusion fluid produced transient monophasic vascoconstrictor responses. In contrast, similarly administered 5-hydroxytryptamine (5-HT) or methysergide caused prolonged biphasic vascoconstrictor responses. The extraluminal/intraluminal potency ratios for noradrenaline, 5-HT and methysergide were 230, 15 and 6 respectively, which indicates that 5-HT and methysergide are relatively more potent when administered extraluminally than noradrenaline. Cocaine (3·10 × 10−5 mol litre−1) markedly increased the potency of extraluminally administered noradrenaline and converted the monophasic responses produced by noradrenaline to biphasic responses. It is concluded that under the experimental conditions used 5-HT and methysergide produced biphasic responses by an action on the medial smooth muscle firstly via the intraluminal surface and secondly an additional direct action via the adventitial surface. Noradrenaline's extraluminal potency is low because of its neuronal uptake and hence the responses are normally monophasic.

A proposed mechanism for the biphasic vasoconstrictor responses to 5-hydroxytryptamine and methysergide in the rabbit ear artery.

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