8-Carboxamidocyclazocine

8-Carboxamidocyclazocine (8-CAC) is an opioid analgesic drug related to cyclazocine, discovered by medicinal chemist Mark P. Wentland and co-workers in Cogswell Laboratory at Rensselaer Polytechnic Institute.[1] Similarly to cyclazocine, 8-CAC acts as an agonist at both the μ and κ opioid receptors, but has a much longer duration of action than cyclazocine, and does not have μ antagonist activity. Unexpectedly it was discovered that the phenolic hydroxyl group of cyclazocine could be replaced by a carboxamido group with only slight loss of potency at opioid receptors, and this discovery has subsequently been used to develop many novel opioid derivatives where the phenolic hydroxy group has been replaced by either carboxamide or a variety of larger groups. Due to their strong κ-opioid agonist activity, these drugs are not suited for use as analgesics in humans, but have instead been researched as potential drugs for the treatment of cocaine addiction.[2][3][4][5][6][7][8][9][10]

8-Carboxamidocyclazocine
Identifiers
  • (1S,10R,13R)-10-(Cyclopropylmethyl)-1,13-dimethyl-10-azatricyclo[7.3.1.02,7]trideca-2(7),3,5-triene-4-carboxamide
CAS Number
PubChem CID
ChemSpider
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC19H26N2O
Molar mass298.430 g·mol−1
3D model (JSmol)
  • C[C@H]1[C@H]2Cc3ccc(cc3[C@]1(CCN2CC4CC4)C)C(=O)N
  • InChI=1S/C19H26N2O/c1-12-17-10-14-5-6-15(18(20)22)9-16(14)19(12,2)7-8-21(17)11-13-3-4-13/h5-6,9,12-13,17H,3-4,7-8,10-11H2,1-2H3,(H2,20,22)/t12-,17+,19-/m0/s1
  • Key:FAVQVALXVLMHLE-WILYLXEWSA-N
  (verify)

See also
  • Tianeptine, an atypical, selective MOR full-agonist licensed for major depression since 1989.
  • Samidorphan, an opioid preferring the MOR, which is under development for major depression.

References
  1. US Patent 6784187 8-carboxamido-2,6-methano-3-benzazocines
  2. Wentland MP, Lou R, Ye Y, Cohen DJ, Richardson GP, Bidlack JM (March 2001). "8-Carboxamidocyclazocine analogues: redefining the structure-activity relationships of 2,6-methano-3-benzazocines". Bioorganic & Medicinal Chemistry Letters. 11 (5): 623–6. doi:10.1016/S0960-894X(01)00014-2. PMID 11266156.
  3. Bidlack JM, Cohen DJ, McLaughlin JP, Lou R, Ye Y, Wentland MP (July 2002). "8-Carboxamidocyclazocine: a long-acting, novel benzomorphan". The Journal of Pharmacology and Experimental Therapeutics. 302 (1): 374–80. doi:10.1124/jpet.302.1.374. PMID 12065740. S2CID 15864569.
  4. Stevenson GW, Wentland MP, Bidlack JM, Mello NK, Negus SS (December 2004). "Effects of the mixed-action kappa/mu opioid agonist 8-carboxamidocyclazocine on cocaine- and food-maintained responding in rhesus monkeys". European Journal of Pharmacology. 506 (2): 133–41. doi:10.1016/j.ejphar.2004.10.051. PMID 15588733.
  5. Wentland MP, VanAlstine M, Kucejko R, Lou R, Cohen DJ, Parkhill AL, Bidlack JM (September 2006). "Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. 4. Opioid receptor binding properties of 8-[N-(4'-phenyl)-phenethyl)carboxamido] analogues of cyclazocine and ethylketocycalzocine". Journal of Medicinal Chemistry. 49 (18): 5635–9. doi:10.1021/jm060278n. PMID 16942039.
  6. VanAlstine MA, Wentland MP, Cohen DJ, Bidlack JM (December 2007). "Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. 5. Opioid receptor binding properties of N-((4'-phenyl)-phenethyl) analogues of 8-CAC". Bioorganic & Medicinal Chemistry Letters. 17 (23): 6516–20. doi:10.1016/j.bmcl.2007.09.082. PMC 2137165. PMID 17935988.
  7. Wentland MP, Sun X, Cohen DJ, Bidlack JM (May 2008). "Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. Part 6: Opioid receptor binding properties of cyclic variants of 8-carboxamidocyclazocine". Bioorganic & Medicinal Chemistry. 16 (10): 5653–64. doi:10.1016/j.bmc.2008.03.066. PMC 2441872. PMID 18417347.
  8. Wentland MP, Lu Q, Ganorkar R, Zhang SZ, Jo S, Cohen DJ, Bidlack JM (January 2009). "Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. Part 7: syntheses and opioid receptor properties of cyclic variants of cyclazocine". Bioorganic & Medicinal Chemistry Letters. 19 (2): 365–8. doi:10.1016/j.bmcl.2008.11.076. PMID 19091564.
  9. Wentland MP, Lou R, Lu Q, Bu Y, Denhardt C, Jin J, et al. (April 2009). "Syntheses of novel high affinity ligands for opioid receptors". Bioorganic & Medicinal Chemistry Letters. 19 (8): 2289–94. doi:10.1016/j.bmcl.2009.02.078. PMC 2791460. PMID 19282177.
  10. Prisinzano TE, Tidgewell K, Harding WW (October 2005). "Kappa opioids as potential treatments for stimulant dependence". The AAPS Journal. 7 (3): E592-9. doi:10.1208/aapsj070361. PMC 2751263. PMID 16353938.
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