β-Chlornaltrexamine

β-Chlornaltrexamine
Clinical data
Other names	β-Chlornaltrexamine; Beta-Chlornaltrexamine; β-CNA; Beta-CNA; Chlornaltrexamine; CNA; 6β-[Bis(2-chloroethyl)amino]-17-(cyclopropylmethyl)-4,5α-epoxymorphinan-3,14-diol
Identifiers
	IUPAC name (4R,4aS,7R,7aR,12bS)-7-[bis(2-chloroethyl)amino]-3-(cyclopropylmethyl)-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,9-diol;
CAS Number	67025-94-9 ;
PubChem CID	5486190;
ChemSpider	4588895 ;
ChEMBL	ChEMBL3228678;
CompTox Dashboard (EPA)	DTXSID90985877 ;
Chemical and physical data
Formula	C24H32Cl2N2O3
Molar mass	467.43 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1C[C@]2([C@H]3CC4=C5[C@@]2(CCN3CC6CC6)[C@H]([C@@H]1N(CCCl)CCCl)OC5=C(C=C4)O)O;
	InChI InChI=1S/C24H32Cl2N2O3/c25-8-11-27(12-9-26)17-5-6-24(30)19-13-16-3-4-18(29)21-20(16)23(24,22(17)31-21)7-10-28(19)14-15-1-2-15/h3-4,15,17,19,22,29-30H,1-2,5-14H2/t17-,19-,22+,23+,24-/m1/s1; Key:OSLQQDMGHVQLCH-HRMPSQMFSA-N;
	(verify)

β-Chlornaltrexamine (β-CNA) is a non-selective irreversible antagonist of the μ-opioid receptor (MOR), the δ-opioid receptor (DOR), and the κ-opioid receptor (KOR), which forms a covalent bond to the binding sites of these receptors and has ultra-long-lasting opioid antagonist effects.^[1] Although it is predominantly antagonistic, β-CNA also shows some irreversible mixed agonist–antagonist activity at the MOR and KOR and some associated analgesic effects.^[2]^[3] Its alkylating group is a bis(chloroalkyl)amino-residue similar to that of the nitrogen mustards.^[4]^[5]^[6]^[7]

The drug was first described by 1978.^[8]^[9] It should not be confused with its epimer and related drug α-chlornaltrexamine (α-CNA), which is likewise predominantly an irreversible antagonist of the opioid receptors but also shows some irreversible mixed agonist–antagonist activity.^[10]

References

^ Ward SJ, Portoghese PS, Takemori AE (June 1982). "Pharmacological profiles of beta-funaltrexamine (beta-FNA) and beta-chlornaltrexamine (beta-CNA) on the mouse vas deferens preparation". Eur J Pharmacol. 80 (4): 377–384. doi:10.1016/0014-2999(82)90083-8. PMID 6286325.
^ Leff P, Dougall IG (September 1988). "Estimation of opioid receptor agonist dissociation constants with beta-chlornaltrexamine, an irreversible ligand which also displays agonism". Br J Pharmacol. 95 (1): 234–240. doi:10.1111/j.1476-5381.1988.tb16569.x. PMC 1854139. PMID 2851350.
^ Broadbear JH, Sumpter TL, Burke TF, Husbands SM, Lewis JW, Woods JH, Traynor JR (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". J Pharmacol Exp Ther. 294 (3): 933–940. PMID 10945843.
^ Portoghese PS, Larson DL, Jiang JB, Takemori AE, Caruso TP (July 1978). "6β-[N,N-Bis(2-chloroethyl)amino]-17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan(chlornaltrexamine) a potent opioid receptor alkylating agent with ultralong narcotic antagonist activity". J. Med. Chem. 21 (7): 598–9. doi:10.1021/jm00205a002. PMID 209185.
^ Portoghese PS, Larson DL, Jiang JB, Caruso TP, Takemori AE (February 1979). "Synthesis and pharmacologic characterization of an alkylating analogue (chlornaltrexamine) of naltrexone with ultralong-lasting narcotic antagonist properties". J. Med. Chem. 22 (2): 168–73. doi:10.1021/jm00188a008. PMID 218009.
^ Caruso TP, Larson DL, Portoghese PS, Takemori AE (June 1980). "Pharmacological studies with an alkylating narcotic agonist, chloroxymorphamine, and antagonist, chlornaltrexamine". J. Pharmacol. Exp. Ther. 213 (3): 539–44. PMID 6162947.
^ Caruso TP, Larson DL, Portoghese PS, Takemori AE (December 1980). "Isolation of selective 3H-chlornaltrexamine-bound complexes, possible opioid receptor components in brains of mice". Life Sci. 27 (22): 2063–9. doi:10.1016/0024-3205(80)90485-3. PMID 6259471.
^ Portoghese PS, Larson DL, Jiang JB, Takemori AE, Caruso TP (July 1978). "6beta-[N,N-Bis(2-chloroethyl)amino]-17-(cyclopropylmethyl)-4,5alpha-epoxy-3,14-dihydroxymorphinan(chlornaltrexamine) a potent opioid receptor alkylating agent with ultralong narcotic antagonist actitivty". J Med Chem. 21 (7): 598–599. doi:10.1021/jm00205a002. PMID 209185.
^ Portoghese PS, Larson DL, Jiang JB, Caruso TP, Takemori AE (February 1979). "Synthesis and pharmacologic characterization of an alkylating analogue (chlornaltrexamine) of naltrexone with ultralong-lasting narcotic antagonist properties". J Med Chem. 22 (2): 168–173. doi:10.1021/jm00188a008. PMID 218009.
^ Sayre LM, Takemori AE, Portoghese PS (April 1983). "Alkylation of opioid receptor subtypes by alpha-chlornaltrexamine produces concurrent irreversible agonistic and irreversible antagonistic activities". J Med Chem. 26 (4): 503–506. doi:10.1021/jm00358a009. PMID 6300401.

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[WardPortogheseTakemori1982-1] Ward SJ, Portoghese PS, Takemori AE (June 1982). "Pharmacological profiles of beta-funaltrexamine (beta-FNA) and beta-chlornaltrexamine (beta-CNA) on the mouse vas deferens preparation". Eur J Pharmacol. 80 (4): 377–384. doi:10.1016/0014-2999(82)90083-8. PMID 6286325.

[LeffDougall1988-2] Leff P, Dougall IG (September 1988). "Estimation of opioid receptor agonist dissociation constants with beta-chlornaltrexamine, an irreversible ligand which also displays agonism". Br J Pharmacol. 95 (1): 234–240. doi:10.1111/j.1476-5381.1988.tb16569.x. PMC 1854139. PMID 2851350.

[BroadbearSumpterBurke2000-3] Broadbear JH, Sumpter TL, Burke TF, Husbands SM, Lewis JW, Woods JH, Traynor JR (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". J Pharmacol Exp Ther. 294 (3): 933–940. PMID 10945843.

[4] Portoghese PS, Larson DL, Jiang JB, Takemori AE, Caruso TP (July 1978). "6β-[N,N-Bis(2-chloroethyl)amino]-17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan(chlornaltrexamine) a potent opioid receptor alkylating agent with ultralong narcotic antagonist activity". J. Med. Chem. 21 (7): 598–9. doi:10.1021/jm00205a002. PMID 209185.

[5] Portoghese PS, Larson DL, Jiang JB, Caruso TP, Takemori AE (February 1979). "Synthesis and pharmacologic characterization of an alkylating analogue (chlornaltrexamine) of naltrexone with ultralong-lasting narcotic antagonist properties". J. Med. Chem. 22 (2): 168–73. doi:10.1021/jm00188a008. PMID 218009.

[6] Caruso TP, Larson DL, Portoghese PS, Takemori AE (June 1980). "Pharmacological studies with an alkylating narcotic agonist, chloroxymorphamine, and antagonist, chlornaltrexamine". J. Pharmacol. Exp. Ther. 213 (3): 539–44. PMID 6162947.

[7] Caruso TP, Larson DL, Portoghese PS, Takemori AE (December 1980). "Isolation of selective 3H-chlornaltrexamine-bound complexes, possible opioid receptor components in brains of mice". Life Sci. 27 (22): 2063–9. doi:10.1016/0024-3205(80)90485-3. PMID 6259471.

[PortogheseLarsonJiang1978-8] Portoghese PS, Larson DL, Jiang JB, Takemori AE, Caruso TP (July 1978). "6beta-[N,N-Bis(2-chloroethyl)amino]-17-(cyclopropylmethyl)-4,5alpha-epoxy-3,14-dihydroxymorphinan(chlornaltrexamine) a potent opioid receptor alkylating agent with ultralong narcotic antagonist actitivty". J Med Chem. 21 (7): 598–599. doi:10.1021/jm00205a002. PMID 209185.

[PortogheseLarsonJiang1979-9] Portoghese PS, Larson DL, Jiang JB, Caruso TP, Takemori AE (February 1979). "Synthesis and pharmacologic characterization of an alkylating analogue (chlornaltrexamine) of naltrexone with ultralong-lasting narcotic antagonist properties". J Med Chem. 22 (2): 168–173. doi:10.1021/jm00188a008. PMID 218009.

[SayreTakemoriPortoghese1983-10] Sayre LM, Takemori AE, Portoghese PS (April 1983). "Alkylation of opioid receptor subtypes by alpha-chlornaltrexamine produces concurrent irreversible agonistic and irreversible antagonistic activities". J Med Chem. 26 (4): 503–506. doi:10.1021/jm00358a009. PMID 6300401.

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See also

References