Pravadoline

{{Short description|Chemical compound}}

{{Drugbox

| Verifiedfields = changed

| verifiedrevid = 464213342

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

| image = Pravadoline.svg

| image_class = skin-invert-image

| tradename =

| pregnancy_AU =

| pregnancy_US =

| pregnancy_category =

| legal_AU =

| legal_CA =

| legal_UK =

| legal_US =

| legal_status = Legal

| routes_of_administration =

| bioavailability =

| protein_bound =

| metabolism =

| elimination_half-life =

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| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 92623-83-1

| ATC_prefix = none

| ATC_suffix =

| PubChem = 56463

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank =

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 50942

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = P3JW662TWA

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 13178

| C=23 | H=26 | N=2 | O=3

| smiles = O=C(c1ccc(OC)cc1)c2c4ccccc4n(c2C)CCN3CCOCC3

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 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

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = MEUQWHZOUDZXHH-UHFFFAOYSA-N

}}

Pravadoline (WIN 48,098) is an anti-inflammatory and analgesic drug with an IC₅₀ of 4.9 μM and a K_i 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).

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 |vauthors=Haubrich DR, etal |title=Pharmacology of pravadoline: a new analgesic agent |journal=J. Pharmacol. Exp. Ther. |volume=255 |issue=2 |pages=511–22 |year=1990 |pmid=2243340 |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 |vauthors=Bell MR, etal |title=Antinociceptive (aminoalkyl)indoles |journal=J. Med. Chem. |volume=34 |issue=3 |pages=1099–110 |year=1991 |pmid=1900533 |doi=10.1021/jm00107a034 }}

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 |vauthors=Everett RM, etal |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=10.1006/faat.1993.1072

}} 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 |vauthors=D'Ambra TE, etal |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=10.1021/jm00079a016 }}{{cite journal |vauthors=Compton DR, etal |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

|url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=1335057}}