Carmoxirole

{{Infobox drug

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| image = Carmoxirole.svg

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| routes_of_administration = Oral

| class = Dopamine D₂ receptor agonist; Antihypertensive agent

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| CAS_number = 98323-83-2

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| PubChem = 57364

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| ChemSpiderID = 51715

| UNII = MRP4P457ZA

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| ChEBI = 64200

| ChEMBL = 70159

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| synonyms = EMD-45609; EMD45609

| IUPAC_name = 3-[4-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)butyl]-1H-indole-5-carboxylic acid

| C=24 | H=26 | N=2 | O=2

| SMILES = C1CN(CC=C1C2=CC=CC=C2)CCCCC3=CNC4=C3C=C(C=C4)C(=O)O

| StdInChI = 1S/C24H26N2O2/c27-24(28)20-9-10-23-22(16-20)21(17-25-23)8-4-5-13-26-14-11-19(12-15-26)18-6-2-1-3-7-18/h1-3,6-7,9-11,16-17,25H,4-5,8,12-15H2,(H,27,28)

| StdInChIKey = AFSOIHMEOKEZJF-UHFFFAOYSA-N

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Carmoxirole ({{Abbrlink|INN|International Nonproprietary Name}}; 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.{{cite journal | vauthors = Haeusler G, Lues I, Minck KO, Schelling P, Seyfried CA | title = Pharmacological basis for antihypertensive therapy with a novel dopamine agonist | journal = European Heart Journal | volume = 13 Suppl D | pages = 129–135 | date = September 1992 | pmid = 1356783 | doi = 10.1093/eurheartj/13.suppl_d.129 }}{{cite journal | vauthors = Velasco M, Luchsinger A | title = Dopamine: pharmacologic and therapeutic aspects | journal = American Journal of Therapeutics | volume = 5 | issue = 1 | pages = 37–43 | date = January 1998 | doi = 10.1097/00045391-199801000-00007 | pmid = 10099036 | url = https://journals.lww.com/americantherapeutics/abstract/1998/01000/dopamine__pharmacologic_and_therapeutic_aspects.7.aspx | url-access = subscription }} It is taken orally.{{cite journal | vauthors = Remme WJ | title = Therapeutic strategies and neurohormonal control in heart failure | journal = European Heart Journal | volume = 15 Suppl D | pages = 129–138 | date = December 1994 | pmid = 7713102 | doi = 10.1093/eurheartj/15.suppl_d.129 | quote = Orally active dopaminergic agents are few, i.e. levodopa, ibopamine and carmoxirole. Of these, ibopamine has been studied most extensively. }}

Pharmacology

Carmoxirole is a potent, selective, and peripherally restricted partial agonist of the dopamine D₂ receptor. It showed about 1,000-fold higher affinity for the dopamine D₂ receptor over the dopamine D₁ receptor. Carmoxirole also showed some affinity for the serotonin 5-HT_1A 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.

The drug has been found to reverse hyperprolactinemia induced by the dopamine D₂ receptor antagonist amisulpride without producing central effects in rats.{{cite journal | vauthors = Lertxundi U, Domingo-Echaburu S, Peral J, García M | title = Antipsychotic Induced Symptomatic Hyperprolactinemia: Are Dopamine Agonists Safe? | journal = Psychopharmacology Bulletin | volume = 44 | issue = 3 | pages = 66–68 | date = September 2011 | pmid = 27738363 | pmc = 5044550 }}{{cite journal | vauthors = Marchese G, Ruiu S, Casti P, Bartholini F, Saba P, Gessa GL, Pani L | title = Carmoxirole is able to reduce amisulpride-induced hyperprolactinemia without affecting its central effect | journal = European Journal of Pharmacology | volume = 447 | issue = 1 | pages = 109–114 | date = June 2002 | pmid = 12106810 | doi = 10.1016/s0014-2999(02)01896-4 | hdl = 11380/1212095 | hdl-access = free }} 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.{{cite journal | vauthors = Remme WJ | title = Dopaminergic agents in heart failure: rebirth of an old concept | journal = Cardiovascular Drugs and Therapy | volume = 15 | issue = 2 | pages = 107–109 | date = March 2001 | pmid = 11669402 | doi = 10.1023/a:1011162510450 | quote = 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. }}{{cite journal | vauthors = Remme WJ | title = Neurohormonal modulation in heart failure: ACE inhibition and beyond | journal = European Heart Journal | volume = 16 Suppl N | pages = 73–78 | date = December 1995 | pmid = 8682065 | doi = 10.1093/eurheartj/16.suppl_n.73 | quote = 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). }}{{cite journal | vauthors = van der Ent M, van den Heuvel AF, Remme WJ | title = Neurohumoral response to carmoxirole, a selective dopamine (D2) receptor agonist, in patients with chronic moderate heart failure | journal = Cardiovascular Drugs and Therapy | volume = 12 | issue = 4 | pages = 387–394 | date = September 1998 | pmid = 9825185 | doi = 10.1023/a:1007776918751 }} This depression in norepinephrine levels was accompanied by improvements in cardiovascular parameters.

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.

History

Carmoxirole was first described in the scientific literature by 1988.{{cite journal | vauthors = Gericke R, Böttcher H | title = Synthese von 3-[4-(1,2,3,6-Tetrahydro-4-phenyl-1-pyridyl)butyl]-5-indolcarbonsäure, eine blutdrucksenkende Verbindung mit neuartigem Wirkprinzip | journal = Liebigs Annalen der Chemie | volume = 1988 | issue = 8 | pages = 749–752 | date = 16 August 1988 | doi = 10.1002/jlac.198819880807 | issn = 0170-2041 }}{{cite journal | vauthors = Haase AF, Greiner HE, Seyfried CA | title = Neurochemical profile of EMD 45609 (Carmoxirole), a dopamine DA₂-receptor agonist | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | date = 1991 | volume = 343 | issue = 6 | pages = 588–594 | pmid = 1682817 | doi = 10.1007/BF00184289 }} It is based on the indolyl-3-butylamine framework, a class of dopamine receptor agonists.{{cite journal |doi= 10.1111/j.1748-1716.1982.tb07168.x |title= Demonstration of a new type of dopamine receptor agonist: An indolyl-3-butylamine. Actions at intact versus supersensitive dopamine receptors in the rat forebrain |date= 1982 |vauthors= Seyfried CA, Fuxe K, Wolf HP, Agnati LF |journal= Acta Physiologica Scandinavica |volume= 116 |issue= 4 |pages= 465–468 |pmid= 7171006 }}