Pravadoline

Drugbox
IUPAC_name = (4-methoxyphenyl)- [2-methyl-1-(2-morpholin-4-ylethyl)indol-3-yl] methanone

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CAS_number = 92623-83-1
ATC_prefix =
ATC_suffix =
PubChem = 56463
DrugBank =
C=23|H=26|N=2|O=3
molecular_weight = 378.46 g/mol
bioavailability =
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legal_status = Legal
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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,cite journal
author=Haubrich DR, Ward SJ, Baizman E, "et al"
title=Pharmacology of pravadoline: a new analgesic agent
journal=J. Pharmacol. Exp. Ther.
volume=255
issue=2
pages=511–22
year=1990
pmid=2243340
doi=
url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2243340] and it was eventually discovered that pravadoline represented the first compound from a novel class of cannabinoid agonists, the aminoalkylindoles.cite journal
author=Bell MR, D'Ambra TE, Kumar V, "et al"
title=Antinociceptive (aminoalkyl)indoles
journal=J. Med. Chem.
volume=34
issue=3
pages=1099–110
year=1991
pmid=1900533
doi=]

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),cite journal
author=Everett RM, Descotes G, Rollin M, "et al"
title=Nephrotoxicity of pravadoline maleate (WIN 48098-6) in dogs: evidence of maleic acid-induced acute tubular necrosis
journal=Fundam Appl Toxicol
volume=21
issue=1
pages=59–65
year=1993
pmid=8365586
doi=
url=http://linkinghub.elsevier.com/retrieve/pii/S0272059083710729] 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.cite journal
author=D'Ambra TE, Estep KG, Bell MR, "et al"
title=Conformationally restrained analogues of pravadoline: nanomolar potent, enantioselective, (aminoalkyl)indole agonists of the cannabinoid receptor
journal=J. Med. Chem.
volume=35
issue=1
pages=124–35
year=1992
pmid=1732519
doi=] cite journal
author=Compton DR, Gold LH, Ward SJ, Balster RL, Martin BR
title=Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from delta 9-tetrahydrocannabinol
journal=J. Pharmacol. Exp. Ther.
volume=263
issue=3
pages=1118–26
year=1992
pmid=1335057
doi=
url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=1335057]

References