Receptor binding profile of R 41 468, A novel antagonist at 5-HT2 receptors

Leysen, Josée E.; Awouters, F.; Kennis, Ludo; Laduron, Pierre M.; Vandenberk, J.; Janßen, Paul

doi:10.1016/0024-3205(81)90747-5

Cited by 829 publications

(226 citation statements)

References 15 publications

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“…Nevertheless, Trendelenburg (1960) suggested that the 5-HT receptor mediating tachycardia was a D-receptor since the tachycardia could be antagonized by (+ )-lysergic acid diethylamide (LSD). It is, however, clear that D-receptors for 5-HT are not a homogeneous group (Feniuk, 1984); furthermore, LSD appears capable of binding to at least two types of 5-HT recognition site (Peroutka & Snyder, 1979;Leysen et al, 1981). In our experiments, both methiothepin (10-100 jg kg -' i.v.…”

Section: Discussionmentioning

confidence: 54%

“…Nevertheless, all three antagonists were effective in doses as low as 10 pg kg-' i.v. The results suggest that the 5-HT receptor mediating bronchoconstriction in the cat can be characterized as a 5-HT2-receptor on the basis that all three antagonists show a high affinity for 5-HT2 recognition sites identified from ligand binding studies (Leysen et al, 1981).…”

Section: Discussionmentioning

confidence: 87%

See 1 more Smart Citation

5‐Carboxamidotryptamine is a selective agonist at 5‐hydroxytryptamine receptors mediating vasodilatation and tachycardia in anaesthetized cats

Connor¹,

Feniuk²,

Humphrey³

et al. 1986

British J Pharmacology

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 87%

5‐Carboxamidotryptamine is a selective agonist at 5‐hydroxytryptamine receptors mediating vasodilatation and tachycardia in anaesthetized cats

Connor¹,

Feniuk²,

Humphrey³

et al. 1986

British J Pharmacology

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“…This implies that capsaicin indirectly causes mast cell degranulation in the development of edema. Furthermore, we demonstrated that ketanserin (15) and LY 53857 (16), the 5-HT2-receptor antagonist, prevent capsaicin-induced mouse ear edema, as well as methysergide (17), a 5-HT1-and 5-HT2-receptor antagonist. However, the effects of 5-HT2-receptor antagonists were characterized by only partial inhibition.…”

Section: Discussionmentioning

confidence: 96%

Participation of Serotonin in Capsaicin-Induced Mouse Ear Edema

Inoue

Nagata

Kinoshita

1995

Japanese Journal of Pharmacology

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ABSTRACT-We investigated the involvement of serotonin (5-HT) in mouse ear edema induced by topical application of capsaicin (250 ,ug/ear). Application of capsaicin to the ear caused degranulation of mast cells in skin connective tissue. Capsaicin-induced ear edema was significantly inhibited by preadministration of 5-HT2 receptor antagonists such as ketanserin (2 mg/kg, i.v.) and LY 53857 (1 mg/kg, i.v.), but not 5-HT1-, 5-HT3-and 5-HT4-receptor antagonists. Intradermal injection of a-methyl 5-HT (5-HT2-receptor agonist) and 5-HT into ear skin produced edema formation more potently than 8-OH-DPAT (5-HT1A agonist) and 2-methyl 5-HT (5-HT3 agonist). 5-HT2 antagonists markedly suppressed the edema response to 5-HT and its receptor agonists, whereas any antagonist for 5-HT1, 5-HT3 and 5-HT4-receptors had no effect. Furthermore, 5-HT2-receptor antagonists partly prevented ear edema in response to substance P (SP), a putative mediator of capsaicin-induced edema, and compound 48/80, a releaser of vasoactive amines from mast cells. These results suggest that 5-HT released from mast cells is partly involved in the development of capsaicin-induced mouse ear edema via 5-HT2 receptors in the ear skin.Keywords: Capsaicin, Serotonin (5-HT), Ear edema (mouse), 5-HT receptor, 5-HT-receptor antagonist Capsaicin (8-methyl-N-vanillyl-6-nonenamide), the pungent substance contained in many red peppers, evokes neurogenic inflammatory responses such as axon reflex vasodilation, plasma extravasation and painful sensitization (1). Topical application of capsaicin to the mouse ear produces neurogenic skin inflammation (2, 3), which may be mediated by neuropeptides including substance P (SP) released through activation of primary afferent sensory neurons. Virus and Gebhart (4) have suggested that in addition to SP, serotonin (5-HT) also plays a role in the pharmacological activity of capsaicin. Others have reported that treatment of newborn rats with capsaicin causes an increase in the concentrations of histamine and 5-HT in the rat skin as a result of changes of the mast cell system in response to the permanent degeneration of sensory nerves (5). In fact, evidence exists to indicate that peripheral nerve endings and mast cells are in close spatial and functional association (6 -8). Previous studies have found that methysergide is effective in inhibiting capsaicin-induced mouse ear edema (3). However, clear evidence for the involvement of 5-HT in capsaicin-induced inflammation is lacking.5-HT receptors have been classified into at least four subtypes: 5-HT1, 5-HT2, 5-HT3 and 5-HT4 (9, 10). Among them, 5-HT2 receptors participate in the increase of cutaneous vascular permeability induced by 5-HT in rats (11, 12). 5-HT3 receptors are located on neurons and elicit depolization which results in transmitter release from parasympathetic, sympathetic, sensory and enteric neurons (13). Recent studies have shown that neuropeptides are partly released by mediation of 5-HT3 receptor from capsaicin-sensitive afferent neurons (14). These evidence sugg...

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“…Whether metergoline exhibits this effect via blocking both 5-HT 2C and a 1 -adrenoceptors is not known, as it has been reported that metergoline also has moderate affinity for a 1 -adrenoceptors. 27 To investigate the involvement of b 1 -and b 2 -adrenoceptors in M2-induced thermogenesis, a low dose of propranolol (1 mg=kg) was used, as at this dose, propranolol is sufficient to block b 1 -and b 2 -adrenoceptors without affecting the b 3 -subtype. 28 A higher dose of propranolol (20 mg=kg) is required to block the b 3 -adrenoceptor subtype.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of the thermogenic effect of Metabolite 2 (BTS 54 505), a major pharmacologically active metabolite of the novel anti-obesity drug, sibutramine

Heal

2002

Int J Obes

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OBJECTIVE:To investigate the pharmacological mechanisms underlying the induction of thermogenesis by Metabolite 2 (M2; BTS 54 505), a major pharmacologically active metabolite of the anti-obesity drug, sibutramine. DESIGN: Adult female Wistar rats were treated with M2 or vehicle, with or without various monoamine receptor antagonists, prazosin, RS79948, metergoline, propranolol and ( þ )butaclamol. MEASUREMENTS: Colonic temperature and food intake at room temperature (21 AE 1 C), thermoregulatory behavioural response, operant responding for exogenous heat at 7 8 C and oxygen consumption at thermoneutrality (29 C). RESULTS: M2 (10 mg=kg, p.o.) significantly increased colonic temperature during the 4.5 h period following drug administration. This effect was abolished by the non-selective 5-HT receptor antagonist, metergoline (1 mg=kg, p.o.), and a 1 -adrenoceptor antagonist, prazosin (1 mg=kg, p.o.), measured at 1.5 -2.5 h post-M2 administration, and was partially antagonized by each antagonist at 3.5 -4.5 h. The non-selective b-adrenoceptor antagonist, propranolol (1 mg=kg, p.o.), had no effect on the M2-induced increase in colonic temperature, whereas at 20 mg=kg (p.o.), propranolol partially inhibited the effect of M2 on colonic temperature. By contrast, the selective a 2 -adrenoceptor antagonist, RS79948 (1 mg=kg, p.o.), and the D2=D1 receptor antagonist, ( þ )butaclamol (200 mg=kg, p.o.), did not alter the effect of M2 on colonic temperature. In the thermoregulatory study, M2 (10 mg=kg, i.p.)-treated rats required significantly less radiant heat at 7 8 C to maintain body temperature, and this effect was not affected by the D2=D1 receptor antagonist ( þ )butaclamol (100 mg=kg 71 , i.p.). The hypophagia induced by M2 (10 mg=kg) measured up to 24 h was partially antagonized by the a 1 -adrenoceptor antagonist, prazosin, whereas metergoline, RS79948, propranolol and ( þ )butaclamol had no effect on M2-induced hypophagia. CONCLUSION: It is concluded that 5-HT, a 1 -and b 3 -adrenoceptors are involved in the induction of thermogenesis by M2, whereas the hypophagic effect is mainly mediated via a 1 -adrenoceptors. These findings are consistent with M2 increasing 5-HT and noradrenaline tone via potent reuptake inhibition which subsequently results in increased efferent sympathetic activity to brown adipose tissue (BAT).

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Receptor binding profile of R 41 468, A novel antagonist at 5-HT2 receptors

Cited by 829 publications

References 15 publications

5‐Carboxamidotryptamine is a selective agonist at 5‐hydroxytryptamine receptors mediating vasodilatation and tachycardia in anaesthetized cats

5‐Carboxamidotryptamine is a selective agonist at 5‐hydroxytryptamine receptors mediating vasodilatation and tachycardia in anaesthetized cats

Participation of Serotonin in Capsaicin-Induced Mouse Ear Edema

Mechanism of the thermogenic effect of Metabolite 2 (BTS 54 505), a major pharmacologically active metabolite of the novel anti-obesity drug, sibutramine

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