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In contrast, the isomers of norfenfluramine exhibited high-to-moderate affinity for 5-HT 2B 27 and 65 nM, d - and l -isomer, respectively and 5-HT 2C receptors 56 and 99 nM but lesser affinity for 5-HT 2A receptors and nM. Based on reported steady-state blood concentrations of norfenfluramine after average clinical doses in humans Caccia et al. In vitro functional assays were used to assess ligand efficacy and potency.
We intentionally used lines expressing modest levels of receptor and exhibiting low receptor reserve. The intrinsic activities of other known 5-HT agonists e. More recently, activation of the ras -MAP kinase pathway has been implicated in the mitogenic and transforming properties of the 5-HT 2B receptor expressed at moderate densities in fibroblasts and endogenously in carcinoid tumors Launay et al.
The 5-HT 2B receptor also mediates important trophic functions in cardiovascular morphogenesis. Because fenfluramine-induced valvular changes are histopathologically identical with those seen after chronic exposure to 5-HT 2 receptor-preferring ergots ergotamine, methysergide , we examined their affinities, along with that of the active metabolite of methysergide, methylergonovine, at the 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors. Methylergonovine concentrations in plasma have been reported to be substantially higher than the parent drug after the oral administration of methysergide; it is postulated to be the main contributor of methysergide efficacy and side effects Muller-Schweinitzer and Tapparelli, All three ergot compounds exhibited high affinity for all three 5-HT 2 receptor subtypes see also Kursar et al.
Although these data collectively are consistent with the hypothesis that the valvular lesions are due to stimulation of myofibroblast mitogenesis via activation of 5-HT 2B receptors, the interaction of norfenfluramine and ergots with other receptor subtypes may also contribute to these changes. Because ergots are known to exert potent vascular effects via 5-HT 1D -like receptors, we examined the interactions of methysergide, ergotamine, methylergonovine, and norfenfluramine at human 5-HT 1D , 5-HT 1E , and 5-HT 1F receptors.
This inactivity of norfenfluramine along with the observation that tryptamines used clinically for migraine e. Some ergot drugs e. However, bromocriptine and dopamine receptor agonists in general have not been associated with valvular heart disease. We repeated the real-time PCR amplifications using random-primed and gene-specific primed cDNA to ensure that oligo dT priming did not bias our results.
The overall patterns of expression were consistent among the various methods: Determination of absolute copy numbers for each gene is difficult because we have no measure of the reverse transcription efficiency. Real-time PCR experiments with RNA isolated from human valves that had been obtained from patients undergoing valve replacement yielded similar results.
It is unclear what cell types reflect the 5-HT 2 receptor transcript expression pattern in the heart valves because RNA from whole tissues was used; future work using in situ hybridization or immunohistochemical techniques may help resolve this question. The combined data suggest that the agonist interaction of norfenfluramine with 5-HT 2B receptors may contribute to the proliferative valvular heart valve disease seen with fenfluramine.
For both fenfluramine- and methysergide-induced cardiomyopathy, our analysis suggests that the primary metabolite of these drugs may be responsible for the myofibroblast proliferation characteristic of this toxicity. Although all three 5-HT 2 receptor subtypes could trigger the cell proliferation characteristic of ergot and norfenfluramine cardiopathy, the 5-HT 2B receptor presents with the most compelling dataset for this role.
The relative absence of 5-HT 2C receptor transcripts in heart valves and the complete lack of agonist activity by methysergide or its metabolite methylergonovine at the 5-HT 2C receptor argue against a role for this receptor subtype in the common valvular pathology caused by ergots and fenfluramine. In contrast, the 5-HT 2A receptor transcript is abundantly expressed in heart valves, and both ergots and norfenfluramine show moderate-to-potent affinity for this receptor subtype. However, this argument rests solely on in vitro potency differences at recombinant receptors.
We cannot exclude a role for the 5-HT 2A receptor without a comprehensive pharmacological analysis e. Characterization of valvular 5-HT 2B and 5-HT 2A receptors was judged impractical for the present study because of the number of pigs needed to obtain sufficient numbers of acutely isolated myofibroblasts in culture. Last, we cannot exclude the possibility that interactions with other molecular targets known or orphan are contributing factors.
Nevertheless, the pharmacological arguments presented herein suggest that direct agonist actions of norfenfluramine at the 5-HT 2B receptor may contribute to this valvular lesion. In summary, agonistic interactions of norfenfluramine with 5-HT 2B receptors, perhaps with modest 5-HT 2A receptor activation, may directly induce mitogenic activities responsible for the cell proliferation and the cardiotoxic effects of fenfluramine in humans.
Corroborating studies are necessary to validate the mechanistic involvement of this receptor and perhaps identify other genetic and environmental factors that predispose certain individuals for this lesion. This understanding will ultimately lead to the design of safer medicines for future therapeutic use.
We also thank Drs. Last, we thank Dr. Send reprint requests to: Box , Wilmington DE We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses. Skip to main content. Rapid Communication Accelerated Communication A. Fitzgerald , Timothy C. Burn , Barry S.
Brown , John P. Patterson , Martha H. Corjay , Patricia A. Link , Ilgar Abbaszade , Jeannine M. Hollis , Brian L. Largent , Paul R. Hartig , Gregory F. Hollis , Paul C. Meunier , Albert J. Robichaud and David W. Molecular Pharmacology January , 57 1 ;. Abstract Dexfenfluramine was approved in the United States for long-term use as an appetite suppressant until it was reported to be associated with valvular heart disease. Phosphoinositide PI Hydrolysis studies. View inline View popup.
Table 1 Norfenfluramine, but not the parent molecule fenfluramine, potently binds to the human 5-HT 2B receptor and other members of the 5-HT 2 receptor subfamily. Table 2 The enantiomers of norfenfluramine are potent agonists at the recombinant human 5-HT 2B receptor. Discussion The goal of the present study was to examine the pharmacology of fenfluramine and its metabolite, norfenfluramine, with 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors, a subfamily of 5-HT receptors implicated in the feeding, cardiovascular, and mitogenic effects of 5-HT.
Footnotes Send reprint requests to: Accepted September 30, Eur J Clin Pharmacol Ann NY Acad Sci Trends Pharmacol Sci Evidence favoring the ternary complex and two-state models of agonist action. N Engl J Med Theories, animal models and emerging therapies. Prog Drug Res Science Wash DC J Biol Chem Comparative stimulation by hallucino-genic drugs.