Metofoline

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Metofoline
Methopholine.svg
Systematic (IUPAC) name
1-[2-(4-chlorophenyl)ethyl]-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline
Clinical data
Legal status
  • Legal
Identifiers
CAS number 2154-02-1 YesY
63937-57-5 (4'-nitromethopholine)
ATC code None
PubChem CID 16538
ChemSpider 15678 YesY
UNII 72L4ZT2W1P YesY
KEGG D04986 YesY
Chemical data
Formula C20H24ClNO2 
Mol. mass 345.87 g/mol
 YesY (what is this?)  (verify)

Methopholine is an opioid analgesic drug discovered in the 1950s by a team of Swiss researchers at Hoffmann-La Roche.[1]

4'-Nitromethopholine

Methopholine is an isoquinoline derivative which is not structurally related to most other opioids.[2] However, its structural similarity to papaverine is notable.

It has around the same efficacy as an analgesic as codeine, and was evaluated for the treatment of postoperative pain.[3][4][5] Methopholine tablets were marketed in the United States under the brand name of Versidyne,[6] but the drug was withdrawn from the market in 1965 due to the occurrence of ophthalmic side-effects and the discovery that it could produce corneal opacities in dogs.[7]

Methopholine has two enantiomers, with the levo (R) enantiomer being the active form, around 3x the potency of codeine, and the (S) enantiomer being inactive.

Analogues where the 4'-chloro group has been replaced by other groups have also been tested, the fluoro derivative being slightly more potent than chloro, and the nitro derivative being most potent of all, with the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]

Synthesis[edit]

Starting material obtained from a Pictet–Spengler reaction.

Methopholine synthesis:[10]

References[edit]

  1. ^ US patent 3067203, "Tetrahydroisoquinoline Derivatives", issued 1962-12-04, assigned to Hoffmann-La Roche 
  2. ^ Feinberg, A. P.; Creese, I.; Snyder, S. H. (1976). "The Opiate Receptor: A Model Explaining Structure-Activity Relationships of Opiate Agonists and Antagonists". Proceedings of the National Academy of Sciences of the United States of America 73 (11): 4215–4219. doi:10.1073/pnas.73.11.4215. PMC 431391. PMID 186791.  edit
  3. ^ Moore, J.; Foldes, F. F.; Davidson, G. M. (1962). "An Evaluation of the Efficacy of Methopholine for the Relief of Postoperative Pain". The American Journal of the Medical Sciences 244: 337–343. PMID 14475666.  edit
  4. ^ Cass, L. J.; Frederik, W. S. (1963). "Methopholine, A New Analgesic Agent". The American Journal of the Medical Sciences 246: 550–557. PMID 14082642.  edit
  5. ^ Sciorelli, G. (1967). "Plasma Levels and Renal Excretion of Unchanged Methopholine in Man". Experientia 23 (11): 934–936. doi:10.1007/bf02136231. PMID 6057015.  edit
  6. ^ VERSIDYNE — ITS USE IN VASCULAR HEADACHE. ROBERT E. RYAN M.D., M.S., B.S. Assoc. Professor Otolaryngology. Headache: The Journal of Head and Face Pain Vol 2 Issue 4 pages 203–208 1963>
  7. ^ Federal Register, March 27, 1965 (30 FR 4083).
  8. ^ Casy, A. F.; Parfitt, R. Y. (1986). Opioid Analgesics, Chemistry and Receptors. New York: Plenum Press. p. 390. ISBN 0-306-42130-5. 
  9. ^ Walter, M.; Besendorf, H.; Schnider, O. (1963). "Synthesen in der Isochinolinreihe. Substituierte 1-[ω-(Nitrophenyl)alkyl]-1,2,3,4-tetrahydro-isochinoline". Helvetica Chimica Acta 46 (4): 1127–1132. doi:10.1002/hlca.19630460405.  edit
  10. ^ Brossi, A.; Besendrof, H.; Pellmont, B.; Walter, M.; Schinder, O. (1960). "Synthesen in der Isochinolinreihe Halogensubstituierte 1-(?-Phenylalkyl)-1,2,3,4-tetrahydro-isochinoline als Analgetica". Helvetica Chimica Acta 43 (6): 1459. doi:10.1002/hlca.19600430603.  edit