Clocinnamox

Clocinnamox
Clinical data
Other names	C-CAM; CCAM; NIH-10443
Identifiers
	IUPAC name (E)-N-[(4R,4aS,7aR,12bR)-3-(cyclopropylmethyl)-9-hydroxy-7-oxo-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-4a-yl]-3-(4-chlorophenyl)prop-2-enamide; or; (2E)-3-(4-chlorophenyl)-N-[(5α)-17-(cyclopropylmethyl)-3-hydroxy-6-oxo-4,5-epoxymorphinan-14-yl]acrylamide;
CAS Number	117332-69-1;
PubChem CID	6540640;
ChemSpider	5022878;
ChEMBL	ChEMBL386492;
Chemical and physical data
Formula	C29H29ClN2O4
Molar mass	505.01 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1CC1CN2CC[C@]34[C@@H]5C(=O)CC[C@]3([C@H]2CC6=C4C(=C(C=C6)O)O5)NC(=O)/C=C/C7=CC=C(C=C7)Cl;
	InChI InChI=1S/C29H29ClN2O4/c30-20-7-3-17(4-8-20)5-10-24(35)31-29-12-11-22(34)27-28(29)13-14-32(16-18-1-2-18)23(29)15-19-6-9-21(33)26(36-27)25(19)28/h3-10,18,23,27,33H,1-2,11-16H2,(H,31,35)/b10-5+/t23-,27+,28+,29-/m1/s1; Key:RAURUSFBVQLAPW-DNIKMYEQSA-N;

Clocinnamox (CCAM or C-CAM; developmental code name NIH-10443) is a selective and irreversible antagonist of the μ-opioid receptor.^[1]^[2] Closely related compounds include methocinnamox (MCAM) and methoclocinnamox (MCCAM).^[1]^[3]^[4]^[5] They were derived via structural modification of buprenorphine.^[6]^[5] Clocinnamox was first described in the scientific literature by 1992.^[7]

^ ^a ^b Woods JH, Lewis JW, Winger G, Butelman E, Broadbear J, Zernig G (1995). "Methoclocinnamox: A μ Partial Agonist With Pharmacotherapeutic Potential for Heroin Abuse". In National Institute on Drug Abuse (ed.). NIDA Research Monograph. DHEW publication. National Institute on Drug Abuse. pp. 195–219. Retrieved 9 August 2024.
^ Filho CB, Del Fabbro L, de Gomes MG, Goes AT, Souza LC, Boeira SP, et al. (January 2013). "Kappa-opioid receptors mediate the antidepressant-like activity of hesperidin in the mouse forced swimming test". European Journal of Pharmacology. 698 (1–3): 286–291. doi:10.1016/j.ejphar.2012.11.003. PMID 23178563.
^ Jordan CG, Kennalley AL, Roberts AL, Nemes KM, Dolma T, Piper BJ (April 2022). "The Potential of Methocinnamox as a Future Treatment for Opioid Use Disorder: A Narrative Review". Pharmacy. 10 (3): 48. doi:10.3390/pharmacy10030048. PMC 9149874. PMID 35645327.
^ Maguire DR, France CP (March 2023). "Behavioral pharmacology of methocinnamox: A potential new treatment for opioid overdose and opioid use disorder". Journal of the Experimental Analysis of Behavior. 119 (2): 392–406. doi:10.1002/jeab.831. PMC 10281830. PMID 36759567.
^ ^a ^b Broadbear JH, Sumpter TL, Burke TF, Husbands SM, Lewis JW, Woods JH, et al. (September 2000). "Methocinnamox is a potent, long-lasting, and selective antagonist of morphine-mediated antinociception in the mouse: comparison with clocinnamox, beta-funaltrexamine, and beta-chlornaltrexamine". The Journal of Pharmacology and Experimental Therapeutics. 294 (3): 933–940. PMID 10945843.
^ Gerak LR, Maguire DR, France CP (2019). "Behavioral Pharmacology of Drugs Acting at Mu Opioid Receptors". Substance Use Disorders. Handbook of Experimental Pharmacology. Vol. 258. Cham: Springer International Publishing. pp. 127–145. doi:10.1007/164_2019_265. ISBN 978-3-030-33678-3. PMID 31451969. Given the advantages of buprenorphine as a treatment for opioid use disorder, additional compounds related to buprenorphine were synthesized in an attempt to reduce its adverse effects (Broadbear et al. 2000). These efforts resulted in the discovery of the mu opioid receptor antagonist methocinnamox (MCAM). Like buprenorphine, MCAM binds pseudoirreversibly to mu opioid receptors; however, it does not appear to produce agonist effects at mu opioid receptors under any conditions. Instead, MCAM produces long-lasting antagonism at mu opioid receptors, as evidenced by attenuation of the antinociceptive effects of morphine in rodents, with the morphine dose-effect curve shifted up to hundredfold rightward (Peckham et al. 2005) and antagonist effects evident for at least 2 days after administration (Broadbear et al. 2000).
^ Comer SD, Burke TF, Lewis JW, Woods JH (September 1992). "Clocinnamox: a novel, systemically-active, irreversible opioid antagonist". The Journal of Pharmacology and Experimental Therapeutics. 262 (3): 1051–1056. PMID 1326622.

[NIDA1995-1] Woods JH, Lewis JW, Winger G, Butelman E, Broadbear J, Zernig G (1995). "Methoclocinnamox: A μ Partial Agonist With Pharmacotherapeutic Potential for Heroin Abuse". In National Institute on Drug Abuse (ed.). NIDA Research Monograph. DHEW publication. National Institute on Drug Abuse. pp. 195–219. Retrieved 9 August 2024.

[2] Filho CB, Del Fabbro L, de Gomes MG, Goes AT, Souza LC, Boeira SP, et al. (January 2013). "Kappa-opioid receptors mediate the antidepressant-like activity of hesperidin in the mouse forced swimming test". European Journal of Pharmacology. 698 (1–3): 286–291. doi:10.1016/j.ejphar.2012.11.003. PMID 23178563.

[JordanKennalleyRoberts2022-3] Jordan CG, Kennalley AL, Roberts AL, Nemes KM, Dolma T, Piper BJ (April 2022). "The Potential of Methocinnamox as a Future Treatment for Opioid Use Disorder: A Narrative Review". Pharmacy. 10 (3): 48. doi:10.3390/pharmacy10030048. PMC 9149874. PMID 35645327.

[MaguireFrance2023-4] Maguire DR, France CP (March 2023). "Behavioral pharmacology of methocinnamox: A potential new treatment for opioid overdose and opioid use disorder". Journal of the Experimental Analysis of Behavior. 119 (2): 392–406. doi:10.1002/jeab.831. PMC 10281830. PMID 36759567.

[BroadbearSumpterBurke2000-5] Broadbear JH, Sumpter TL, Burke TF, Husbands SM, Lewis JW, Woods JH, et al. (September 2000). "Methocinnamox is a potent, long-lasting, and selective antagonist of morphine-mediated antinociception in the mouse: comparison with clocinnamox, beta-funaltrexamine, and beta-chlornaltrexamine". The Journal of Pharmacology and Experimental Therapeutics. 294 (3): 933–940. PMID 10945843.

[GerakMaguireFrance2019-6] Gerak LR, Maguire DR, France CP (2019). "Behavioral Pharmacology of Drugs Acting at Mu Opioid Receptors". Substance Use Disorders. Handbook of Experimental Pharmacology. Vol. 258. Cham: Springer International Publishing. pp. 127–145. doi:10.1007/164_2019_265. ISBN 978-3-030-33678-3. PMID 31451969. Given the advantages of buprenorphine as a treatment for opioid use disorder, additional compounds related to buprenorphine were synthesized in an attempt to reduce its adverse effects (Broadbear et al. 2000). These efforts resulted in the discovery of the mu opioid receptor antagonist methocinnamox (MCAM). Like buprenorphine, MCAM binds pseudoirreversibly to mu opioid receptors; however, it does not appear to produce agonist effects at mu opioid receptors under any conditions. Instead, MCAM produces long-lasting antagonism at mu opioid receptors, as evidenced by attenuation of the antinociceptive effects of morphine in rodents, with the morphine dose-effect curve shifted up to hundredfold rightward (Peckham et al. 2005) and antagonist effects evident for at least 2 days after administration (Broadbear et al. 2000).

[ComerBurkeLewis1992-7] Comer SD, Burke TF, Lewis JW, Woods JH (September 1992). "Clocinnamox: a novel, systemically-active, irreversible opioid antagonist". The Journal of Pharmacology and Experimental Therapeutics. 262 (3): 1051–1056. PMID 1326622.

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