Carmoxirole
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| Other names | EMD-45609; EMD45609 |
| Routes of administration | Oral[1] |
| Drug class | Dopamine D2 receptor agonist; Antihypertensive agent |
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| Formula | C24H26N2O2 |
| Molar mass | 374.484 g·mol−1 |
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Carmoxirole (INN; developmental code name EMD-45609) is a dopamine D2 receptor agonist which was developed as a potential antihypertensive and heart failure medication but was never marketed.[2][3][4][5] It is taken orally.[1]
Pharmacology
[edit]Carmoxirole is a potent, selective, and peripherally restricted partial agonist of the dopamine D2 receptor.[2][3] It showed about 1,000-fold higher affinity for the dopamine D2 receptor over the dopamine D1 receptor.[2] Carmoxirole also showed some affinity for the serotonin 5-HT1A receptor and for the α2-adrenergic receptor, whereas affinity for other receptors like the serotonin 5-HT2, α1-adrenergic, and β-adrenergic receptors was negligible.[2]
The drug has been found to reverse hyperprolactinemia induced by the dopamine D2 receptor antagonist amisulpride without producing central effects in rats.[6][7] It has also been found to reduce circulating norepinephrine levels by 55% in people with severe heart failure, an action thought to be mediated by its dopamine D2 receptor agonism in the periphery.[4][5][8] This depression in norepinephrine levels was accompanied by improvements in cardiovascular parameters.[4][5]
Chemistry
[edit]Carmoxirole is an indole derivative and shows similarities in its chemical structure to tryptamines and pertines like oxypertine but has an elongated alkyl side chain and hence does not belong to these groups itself.[2]
History
[edit]Carmoxirole was first described in the scientific literature by 1988.[9][10] It is based on the indolyl-3-butylamine framework, a class of dopamine receptor agonists.[11]
See also
[edit]References
[edit]- ^ a b Remme WJ (December 1994). "Therapeutic strategies and neurohormonal control in heart failure". European Heart Journal. 15 Suppl D: 129–138. doi:10.1093/eurheartj/15.suppl_d.129. PMID 7713102.
Orally active dopaminergic agents are few, i.e. levodopa, ibopamine and carmoxirole. Of these, ibopamine has been studied most extensively.
- ^ a b c d e Haeusler G, Lues I, Minck KO, Schelling P, Seyfried CA (September 1992). "Pharmacological basis for antihypertensive therapy with a novel dopamine agonist". European Heart Journal. 13 Suppl D: 129–135. doi:10.1093/eurheartj/13.suppl_d.129. PMID 1356783.
- ^ a b Velasco M, Luchsinger A (January 1998). "Dopamine: pharmacologic and therapeutic aspects". American Journal of Therapeutics. 5 (1): 37–43. PMID 10099036.
- ^ a b c Remme WJ (March 2001). "Dopaminergic agents in heart failure: rebirth of an old concept". Cardiovascular Drugs and Therapy. 15 (2): 107–109. doi:10.1023/a:1011162510450. PMID 11669402.
That DA2 stimulation may lead to a significant reduction in plasma norepinephrine levels in heart failure, was reported already by van der Ent et al. in this journal several years ago [9]. In their study, acute intravenous administration of the selective DA2 agonist carmoxirole decreased circulating norepinephrine by 55% in patients with severe heart failure, accompanied by a significant improvement in cardiac pump function and reduced LV filling pressures.
- ^ a b c Remme WJ (December 1995). "Neurohormonal modulation in heart failure: ACE inhibition and beyond". European Heart Journal. 16 Suppl N: 73–78. doi:10.1093/eurheartj/16.suppl_n.73. PMID 8682065.
Activation of neuronal dopaminergic D2 receptors inhibits the release of noradrenaline in the synaptic cleft and reduces sympathetic activity. In addition, activation of D2 receptors in the adrenal cortex results in aldosterone suppression. Selective D2 agonists therefore may be useful in heart failure. Currently, scant data are available in humans. Carmoxirole, a specific D2 agonist, acutely reduces circulating noradrenaline levels; this is accompanied by significant improvements in cardiac pump function, left and right ventricular filling pressures, and circulating atrial natriuretic peptide levels (personal communication, M. Van der Ent).
- ^ Lertxundi U, Domingo-Echaburu S, Peral J, García M (September 2011). "Antipsychotic Induced Symptomatic Hyperprolactinemia: Are Dopamine Agonists Safe?". Psychopharmacology Bulletin. 44 (3): 66–68. PMC 5044550. PMID 27738363.
- ^ Marchese G, Ruiu S, Casti P, Bartholini F, Saba P, Gessa GL, et al. (June 2002). "Carmoxirole is able to reduce amisulpride-induced hyperprolactinemia without affecting its central effect". European Journal of Pharmacology. 447 (1): 109–114. doi:10.1016/s0014-2999(02)01896-4. PMID 12106810.
- ^ van der Ent M, van den Heuvel AF, Remme WJ (September 1998). "Neurohumoral response to carmoxirole, a selective dopamine (D2) receptor agonist, in patients with chronic moderate heart failure". Cardiovascular Drugs and Therapy. 12 (4): 387–394. doi:10.1023/a:1007776918751. PMID 9825185.
- ^ Gericke R, Böttcher H (16 August 1988). "Synthese von 3-[4-(1,2,3,6-Tetrahydro-4-phenyl-1-pyridyl)butyl]-5-indolcarbonsäure, eine blutdrucksenkende Verbindung mit neuartigem Wirkprinzip". Liebigs Annalen der Chemie. 1988 (8): 749–752. doi:10.1002/jlac.198819880807. ISSN 0170-2041.
- ^ Haase AF, Greiner HE, Seyfried CA (1991). "Neurochemical profile of EMD 45609 (Carmoxirole), a dopamine DA2-receptor agonist". Naunyn-Schmiedeberg's Archives of Pharmacology. 343 (6): 588–594. doi:10.1007/BF00184289. PMID 1682817.
- ^ Seyfried CA, Fuxe K, Wolf HP, Agnati LF (1982). "Demonstration of a new type of dopamine receptor agonist: An indolyl-3-butylamine. Actions at intact versus supersensitive dopamine receptors in the rat forebrain". Acta Physiologica Scandinavica. 116 (4): 465–468. doi:10.1111/j.1748-1716.1982.tb07168.x.