Pravadoline

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Pravadoline
File:Pravadoline.svg
Systematic (IUPAC) name
(4-methoxyphenyl)-[2-methyl-1-(2-morpholin-4-ylethyl)indol-3-yl]methanone
Legal status
Legal status
  • Legal
Identifiers
CAS Number 92623-83-1
ATC code none
PubChem CID 56463
Chemical data
Formula C23H26N2O3
Molar mass 378.46 g/mol[[Script error: No such module "String".]]
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Pravadoline (WIN 48098) is an antiinflammatory and analgesic drug, related in structure to non-steroidal antinflammtory drugs (NSAIDs) such as indometacin. It was developed in the 1980s as a new antiinflammatory and prostaglandin synthesis inhibitor, acting through inhibition of the enzyme cyclooxygenase (COX).

However pravadoline was found to exhibit unexpectedly strong analgesic effects, which appeared at doses ten times smaller than the effective anti-inflammatory dose and so could not be explained by its action as a COX inhibitor. These effects were not blocked by opioid antagonists such as naloxone,[1] and it was eventually discovered that pravadoline represented the first compound from a novel class of cannabinoid agonists, the aminoalkylindoles.[2]

Pravadoline was never developed for use as an analgesic, partly due to toxicity concerns (although these were later shown to be a result of the salt form that the drug had been prepared in rather than from the pravadoline itself),[3] however the discovery of cannabinoid activity in this structurally novel family of drugs led to the discovery of several new cannabinoid agonists, including the drug WIN 55,212-2 which is now widely used in scientific research.[4][5]

References

  1. ↑ Haubrich DR, Ward SJ, Baizman E; et al. (1990). "Pharmacology of pravadoline: a new analgesic agent". J. Pharmacol. Exp. Ther. 255 (2): 511–22. PMID 2243340. 
  2. ↑ Bell MR, D'Ambra TE, Kumar V; et al. (1991). "Antinociceptive (aminoalkyl)indoles". J. Med. Chem. 34 (3): 1099–110. doi:10.1021/jm00107a034. PMID 1900533. 
  3. ↑ Everett RM, Descotes G, Rollin M; et al. (1993). "Nephrotoxicity of pravadoline maleate (WIN 48098-6) in dogs: evidence of maleic acid-induced acute tubular necrosis". Fundam Appl Toxicol. 21 (1): 59–65. doi:10.1006/faat.1993.1072. PMID 8365586. 
  4. ↑ D'Ambra TE, Estep KG, Bell MR; et al. (1992). "Conformationally restrained analogues of pravadoline: nanomolar potent, enantioselective, (aminoalkyl)indole agonists of the cannabinoid receptor". J. Med. Chem. 35 (1): 124–35. doi:10.1021/jm00079a016. PMID 1732519. 
  5. ↑ Compton DR, Gold LH, Ward SJ, Balster RL, Martin BR (1992). "Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from delta 9-tetrahydrocannabinol". J. Pharmacol. Exp. Ther. 263 (3): 1118–26. PMID 1335057. 
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