Metofoline (
INN), also known as methofoline (
USAN), is an
opioidanalgesic drug discovered in the 1950s by a team of Swiss researchers at Hoffmann-La Roche.[1]
Methopholine is an
isoquinoline derivative which is not structurally related to most other opioids.[2]
However, its structural similarity to the non-opioid alkaloid
papaverine is notable.
Metofoline has around the same efficacy as an analgesic as
codeine, and was evaluated for the treatment of postoperative pain.[3][4][5] Metofoline tablets were marketed in the United States under the brand name of Versidyne,[6] but the drug was withdrawn from the market in 1965 due to the occurrence of
ophthalmic side-effects alongside the discovery that the drug could produce
cataracts in dogs.[7]
Metofoline has two
enantiomers, with the levo (R) enantiomer being the active form, around 3x the potency of codeine, and the (S) enantiomer being inactive.
Analogs where the 4'-chloro group has been replaced by other
electron withdrawing groups have also been tested, the fluoro derivative being slightly more potent than chloro, and the nitro derivative being most potent of all, with the racemic 4'-nitromethopholine being around 20x the potency of codeine.[8][9]
Later research was carried out by Bristol-Myer in the 1960s[10] and animal studies suggested derivatives with significantly increased analgesic activity of over x50 codeine.[11]
^Moore J, Foldes FF, Davidson GM (September 1962). "An evaluation of the efficacy of methopholine for the relief of postoperative pain". The American Journal of the Medical Sciences. 244 (3): 337–43.
doi:
10.1097/00000441-196209000-00010.
PMID14475666.
S2CID36562481.
^Cass LJ, Frederik WS (November 1963). "Methopholine, A New Analgesic Agent". The American Journal of the Medical Sciences. 246 (5): 550–7.
doi:
10.1097/00000441-196311000-00005.
PMID14082642.
^'Tetrahydroisoquinolines. I. The Preparation and Analgesic Activity of Some 1-Thiophenoxyethyltetrahydroisoquinolines and 1-Phenoxyethyltetrahydroisoquinolines'J. Med. Chem. 1969 Jul;12(4):575-80. doi: 10.1021/jm00304a003.