Chemistry:Carmoxirole

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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.[1][2][3][4] It is taken orally.[5]

Pharmacology

Carmoxirole is a potent, selective, and peripherally restricted partial agonist of the dopamine D2 receptor.[1][2] It showed about 1,000-fold higher affinity for the dopamine D2 receptor over the dopamine D1 receptor.[1] 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.[1]

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.[3][4][8] This depression in norepinephrine levels was accompanied by improvements in cardiovascular parameters.[3][4]

Chemistry

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.[1]

History

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

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "Pharmacological basis for antihypertensive therapy with a novel dopamine agonist". European Heart Journal 13 Suppl D: 129–135. September 1992. doi:10.1093/eurheartj/13.suppl_d.129. PMID 1356783. 
  2. ↑ 2.0 2.1 "Dopamine: pharmacologic and therapeutic aspects". American Journal of Therapeutics 5 (1): 37–43. January 1998. doi:10.1097/00045391-199801000-00007. PMID 10099036. https://journals.lww.com/americantherapeutics/abstract/1998/01000/dopamine__pharmacologic_and_therapeutic_aspects.7.aspx. 
  3. ↑ 3.0 3.1 3.2 "Dopaminergic agents in heart failure: rebirth of an old concept". Cardiovascular Drugs and Therapy 15 (2): 107–109. March 2001. 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.". 
  4. ↑ 4.0 4.1 4.2 "Neurohormonal modulation in heart failure: ACE inhibition and beyond". European Heart Journal 16 Suppl N: 73–78. December 1995. 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).". 
  5. ↑ "Therapeutic strategies and neurohormonal control in heart failure". European Heart Journal 15 Suppl D: 129–138. December 1994. 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.". 
  6. ↑ "Antipsychotic Induced Symptomatic Hyperprolactinemia: Are Dopamine Agonists Safe?". Psychopharmacology Bulletin 44 (3): 66–68. September 2011. doi:10.64719/pb.4078. PMID 27738363. 
  7. ↑ "Carmoxirole is able to reduce amisulpride-induced hyperprolactinemia without affecting its central effect". European Journal of Pharmacology 447 (1): 109–114. June 2002. doi:10.1016/s0014-2999(02)01896-4. PMID 12106810. 
  8. ↑ "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. September 1998. doi:10.1023/a:1007776918751. PMID 9825185. 
  9. ↑ "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. 16 August 1988. doi:10.1002/jlac.198819880807. ISSN 0170-2041. 
  10. ↑ "Neurochemical profile of EMD 45609 (Carmoxirole), a dopamine DA2-receptor agonist". Naunyn-Schmiedeberg's Archives of Pharmacology 343 (6): 588–594. 1991. doi:10.1007/BF00184289. PMID 1682817. 
  11. ↑ "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. 1982. doi:10.1111/j.1748-1716.1982.tb07168.x. PMID 7171006. 



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