Pravadoline

Pravadoline (WIN 48,098) is an antinflammatory and analgesic drug with an IC50 of 4.9 μM and a Ki of 2511 nM at CB1, related in structure to nonsteroidal anti-inflammatory 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).

Pravadoline
Clinical data
ATC code
  • none
Legal status
Legal status
  • In general: legal
Identifiers
IUPAC name
  • (4-Methoxyphenyl)-[2-methyl-1-(2-morpholin-4-ylethyl)indol-3-yl]methanone
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC23H26N2O3
Molar mass378.472 g·mol−1
3D model (JSmol)
SMILES
  • O=C(c1ccc(OC)cc1)c2c4ccccc4n(c2C)CCN3CCOCC3
InChI
  • InChI=1S/C23H26N2O3/c1-17-22(23(26)18-7-9-19(27-2)10-8-18)20-5-3-4-6-21(20)25(17)12-11-24-13-15-28-16-14-24/h3-10H,11-16H2,1-2H3 Y
  • Key:MEUQWHZOUDZXHH-UHFFFAOYSA-N Y
 NY (what is this?)  (verify)

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]

Animal studies

Administration of pravadoline on rats showed:[1]

  • Prolonged the response latency induced by tail immersion in hot water at a temperature of 55 °C (minimum effective dose 100 mg/kg s.c.)
  • Prevented hyperalgesia in rats with brewer's yeast injections during (Randall-Selitto test) (minimum effective dose 1 mg/kg, p.o.)
  • Prevented the nociceptive response induced by paw flexion in the adjuvant-arthritic rat (ED50 41 mg/kg, p.o.)
  • Prevented the nociceptive response of bradykinin-induced head and forepaw flexion (ED50 78 mg/kg, p.o.)

The antinociceptive activity of pravadoline cannot be explained by an opioid mechanism, because pravadoline-induced antinociception was not antagonized by naloxone (1 mg/kg, s.c.) and pravadoline did not bind to the opioid receptors at concentrations up to 10 μM.[1]

See also

References
  1. Haubrich DR, et al. (1990). "Pharmacology of pravadoline: a new analgesic agent". J. Pharmacol. Exp. Ther. 255 (2): 511–22. PMID 2243340.
  2. Bell MR, et al. (1991). "Antinociceptive (aminoalkyl)indoles". J. Med. Chem. 34 (3): 1099–110. doi:10.1021/jm00107a034. PMID 1900533.
  3. Everett RM, 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, 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, et al. (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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