Is migraine prophylactic activity caused by 5-HT2B or 5-HT2C receptor blockade?

doi:10.1016/0024-3205(94)00546-X

Life Sciences

Volume 54, Issue 10, 1994, Pages 641-644

https://doi.org/10.1016/0024-3205(94)00546-X Get rights and content

Abstract

It has been suggested that activation of 5-HT_2C receptors is involved in the initiation of a migraine attack. The 5-HT_2C receptor and the newly cloned rat fundus 5-HT_2B receptor show close pharmacological and structural resemblance. Antagonist pA₂ values from the rat stomach and pK_D values from a 5-HT_2C receptor binding assay correlated both highly significantly (p 0< 0.005) with the daily dose of eight migraine prophylactic compounds. Although the small difference in antimigraine potency between the enantiomers of propranolol agrees with the lack of stereo-selectivity found on the rat fundus 5-HT_2B receptor but not with the 5-HT_2C receptor, the evidence available does not allow one to distinguish between 5-HT_2C and 5-HT_2B receptor blockade as possible mechanisms for prophylactic activity.

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Cited by (74)

Serotonin and cardiovascular diseases
2018, Serotonin: The Mediator that Spans Evolution
Serotonergic dysfunction is mainly associated with neuropsychiatric and cardiovascular disorders but has also been linked with many other pathological conditions. This review provides an overview of the recent pharmacological developments involving 5-hydroxytryptamine (5-HT; serotonin), released from blood platelets, in the human cardiovascular system. The acute cardiovascular response to serotonin, named the Bezold–Jarisch reflex, leads to intense bradycardia associated with atrioventricular block and involves 5-HT₃, 5-HT_1B, 5-HT₇, and 5-HT_2A/2B receptors. The contribution of serotonin and its receptors (5-HT₄ and 5-HT_2A/2B) in cardiac development, in cardiovascular tissue remodeling, with a particular emphasis on cardiac hypertrophy, fibrosis, and failure, in valve degeneration is explored in this review. Some new aspects of 5-HT_1B, 5-HT₇, and 5-HT_2A/2B receptors in vasomotor tone regulation and the interaction between endothelial and smooth muscle cells are also be discussed. As well, serotonin, its transporter, 5-HT_1B, and 5-HT_2B receptors participation in pulmonary hypertension and pulmonary vascular remodeling are presented. Finally, the contribution of bone marrow (BM)-derived endothelial progenitors in the pathogenesis of pulmonary hypertension and interactions with bone morphogenic protein (BMP) type 2 receptor signaling are highlighted.
The aim of this review is thus to emphasize the vascular, cardiac, and pulmonary effects caused by serotonin receptor activation and to highlight their possible prevention by the development of new drugs targeting this system.
BF-1 - A novel selective 5-HT<inf>2B</inf> receptor antagonist blocking neurogenic dural plasma protein extravasation in guinea pigs
2015, European Journal of Pharmacology
Citation Excerpt :
While the need for acute migraine treatment is fairly well served by triptans, ergotamines, anticonvulsants, non-steroidal anti-inflammatory drugs (NSAIDs) or β-blockers, prophylactic treatment is far from satisfactory. Several pharmaceutical agents have been applied in prophylactic migraine treatment, such as propranolol ((RS)-1-(isopropylamino)-3-(naphthalen-1-yloxy)propan-2-ol), methysergide, pizotifen or amitriptyline (3-(10,11-Dihydro-5H-dibenzo[a,d] cyclohepten-5-yliden)-N,N-dimethylpropylamin) (Fozard and Kalkmann, 1994; Kalkman, 1994; Fozard, 1995). They share antagonistic potency at 5-HT2B receptors, which is believed to be responsible for the effect (Schmuck et al., 1996).
Serotonin 5-HT_2B receptor antagonists have been proposed as migraine prophylactic drugs, but previously available 5-HT_2B receptor antagonists displayed multiple monoaminergic side effects and had to be withdrawn from the market. Here, we set out to identify a novel antagonist with high affinity and selectivity towards 5-HT_2B receptors. To test the affinity of new compounds towards various receptors, we generated a broad series of cells functionally coupling human monoaminergic receptors to luciferase. Using the cell lines we revealed pimethixene (1-methyl-4-(9H-thioxanthen-9-ylidene)piperidine) as highly potent, albeit non-selective 5-HT_2B receptor antagonist and optimized its chemical structure to create highly potent and selective 5-HT_2B receptor antagonists. We selected the methoxythioxanthene BF-1 for further analysis. In comparison to pimethixene, it lacked high affinities to 5-HT_1A, 5-HT_2A, 5-HT_2C, histamine H₁, dopamine D₁ and D₂ as well as muscarinic M₁ and M₂ receptors. BF-1 was tested as potential migraine prophylactic drug by blocking meta-chlorophenylpiperazine, (mCPP) or BW723C86 (5-((thiophen-2-yl)methoxy)-α-methyltryptamine) induced neurogenic dural plasma protein extravasation in a guinea pig model that may resemble a migraine attack. BF-1 was significantly more potent in this assay compared to the well know non-selective 5-HT_2B antagonists, methysergide ((6aR,9R)-N-[(2S)-1-Hydroxybutan-2-yl]-4,7-dimethyl-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxamide) or pizotifen (4-(1-methyl-4-piperidylidine)-9,10-dihydro-4H-benzo-[4,5]cyclohepta[1,2]-thiophene). Therefore, we propose BF-1 as a new compound that may be developed for prophylactic migraine treatment without the typical monoaminergic side effects.
Psilocybin dose-dependently causes delayed, transient headaches in healthy volunteers
2012, Drug and Alcohol Dependence
Citation Excerpt :
Receptors that trigger migraine attack (possibly 5-HT2B) appear to be different from those that relieve migraine headache (5-HT1 family). The ability of the 5-HT2B/C receptor agonist m-chlorophenylpiperazine (mCPP) to induce attacks in migraine sufferers that are indistinguishable from spontaneous headaches (Brewerton et al., 1988), together with the 5-HT2B affinity of prophylactic antimigraine 5-HT2 receptor antagonists such as methysergide, cyproheptadine, and mianserin, support the involvement of 5-HT2B supersensitivity in migraine attacks (Fozard and Kalkman, 1994; Kalkman, 1994; Schmuck et al., 1996). Triptans are a novel class of selective 5-HT1B/1D antagonists that are the mainstay of current acute migraine treatment.
Psilocybin is a well-characterized classic hallucinogen (psychedelic) with a long history of religious use by indigenous cultures, and nonmedical use in modern societies. Although psilocybin is structurally related to migraine medications, and case studies suggest that psilocybin may be efficacious in treatment of cluster headache, little is known about the relationship between psilocybin and headache.
This double-blind study examined a broad range of psilocybin doses (0, 5, 10, 20, and 30 mg/70 kg) on headache in 18 healthy participants.
Psilocybin frequently caused headache, the incidence, duration, and severity of which increased in a dose-dependent manner. All headaches had delayed onset, were transient, and lasted no more than a day after psilocybin administration.
Possible mechanisms for these observations are discussed, and include induction of delayed headache through nitric oxide release. These data suggest that headache is an adverse event to be expected with the nonmedical use of psilocybin-containing mushrooms as well as the administration of psilocybin in human research. Headaches were neither severe nor disabling, and should not present a barrier to future psilocybin research.
Pathophysiological basis of migraine prophylaxis
2009, Progress in Neurobiology
Several cellular and molecular mechanisms have been implicated in migraine pathophysiology including abnormal neuronal excitability and vascular events. Drugs from different pharmacological classes are used for migraine prophylaxis. These agents may normalize neuronal excitability by modulating distinct ionic channels and various neurotransmitter systems. They can also block cortical spreading depression, prevent peripheral and/or central pain sensitization, and normalize brainstem function. Most of the drugs recently used in migraine prophylaxis have been identified by serendipidy and they have been originally approved for other indications. Subsequently, their use has been extended to migraine prevention, according to their putative mechanisms of action. More recently, trials on adequate samples of migraine patients have been conducted for several drugs. In the present review, we will present and discuss the pathophysiological bases for the use of antidepressants, β-adrenergic blockers, calcium channel blockers and antiepileptic drugs in migraine prevention. Currently, the major classes of conventional migraine preventive drugs include the antidepressant amitriptyline, the β-adrenergic blocker propranolol, and the antiepileptic drugs topiramate and valproic acid. Promising results have recently been obtained for angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor blockers. Some limited clinical findings have also been reported for atypical antipsychotic agents, nutritional supplements and also botulinum toxin. Targets of migraine preventive treatment are to reduce frequency and intensity of attacks and to decrease disability related to chronic headache.
Neurogenic Vascular Responses in the Dura Mater and their Relevance for the Pathophysiology of Headaches
2009, NeuroImmune Biology
Citation Excerpt :
It is therefore not surprising that 5-HT receptor agonists can either initiate or abort migraine attacks. Cerebrovascular endothelial 5-HT2B receptors have been suggested to be activated at the beginning of a migraine attack [107,108]. 5-HT2 receptor antagonists are therefore used in the prophylaxis of migraine.
Neurogenic inflammation of the dura mater encephali is considered to be involved in the generation of primary vascular headaches. Different components of neurogenic inflammation – increased blood flow and vascular permeability, activation of endothelial and mast cells – seem to have differential significance in the pathophysiology of primary headaches. While the release of vasoactive substances from primary sensory neurons, endothelium, or mast cells has clearly been shown to occur during headache attacks, vascular permeability changes seem not to play any role. Clinical and experimental observations indicate that the sensory neuropeptide calcitonin gene-related peptide (CGRP) has a key position in meningeal vasodilatation. Beside its direct vasorelaxant effect, CGRP releases the inflammatory mediator histamine from mast cells and interacts with another potent vasodilator, nitric oxide, originating mainly from dural endothelial cells. Parasympathetic nerve fibers of the dura mater are also activated in some types of primary headaches, possibly by a trigeminal-parasympathetic reflex involving brain stem mechanisms. Interactions between different vasoactive regulators of meningeal blood flow may contribute to the pathogenesis of primary headaches.
Neuroleptics in the treatment of migraine
2008, Medicina Clinica

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MinireviewIs migraine prophylactic activity caused by 5-HT2B or 5-HT2C receptor blockade?

Abstract

Trends Pharmacol. Sci.

Trends Pharmacol. Sci.

Eur. J. Pharmacol.

Clin. Pharmacol. Ther.

EMBO J.

Mol. Pharmacol.

J. Recept. Res.

J. Pharm. Pharmacol.

Br. J. Pharmacol.

Br. J. Pharmacol.

Pharmazie

Minireview
Is migraine prophylactic activity caused by 5-HT_2B or 5-HT_2C receptor blockade?