U-77891
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| Routes of administration | oral, parenteral |
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| Chemical and physical data | |
| Formula | C17H22Br2N2O |
| Molar mass | 430.184 g·mol−1 |
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U-77891 was synthesized in 1983 by the the Upjohn company [1] to prove that the removal of a single methylene spacer of the benzamide would alter a κ-opioid receptor agonist such as U-50488 into a μ-opioid receptor agonist and to produce a semi-rigid derivative of U-47700 so that the relative positions of the hydrogen-bond acceptors and substituted aromatic system to find the compound with the lowest Ki value of a series of benzamide opioids dating back to the 1970s[2]. The synthesis is accomplished in 11 steps (including resolution of the trans isomers).
The trans isomers (active) This compound has a Ki of 2 at the μ receptor & a Ki of 2300 at the κ receptor (a selectivity of 1650). The compound has an ED50 of 0.02mg/kg (writhing (sc)) & 0.21mg/kg (tail-flick (sc)) in animal studies. One reason for the potency is the high LogP of 4.34 means it accumulates in fatty tissue such as the brain The inactive cis isomer is removed by the formation of the fumarate salt.
References
- ^ US Patent 45980882-Pyrroloyl-cycloalkyl-amide analgesics - J Szmuszkovicz, JM McCall, LJ Kaplan, Joseph W. McMillan
- ^ Roger A. Fujimoto, Jerome Boxer, Robert H. Jackson, John P. Simke, Robert F. Neale, Elaine W. Snowhill, Beverly J. Barbaz, Michael Williams, Matthew A. Sills (June 1989). "Synthesis, opioid receptor binding profile, and antinociceptive activity of 1-azaspiro[4.5]decan-10-yl amides". Journal of Medicnal Chemistry. 32 (6): 1259–1265. doi:10.1021/jm00126a019. PMID 2542556.
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