Metofoline

Metofoline
Clinical data
ATC code	none;
Legal status
Legal status	In general: legal;
Identifiers
	IUPAC name 1-[2-(4-chlorophenyl)ethyl]-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline;
CAS Number	2154-02-1 ; 63937-57-5 (4'-nitromethopholine);
PubChem CID	16538;
ChemSpider	15678 ;
UNII	72L4ZT2W1P;
KEGG	D04986 ;
Chemical and physical data
Formula	C20H24ClNO2
Molar mass	345.87 g/mol g·mol−1
3D model (JSmol)	Interactive image;
	SMILES ClC1=CC=C(CCC2C3=CC(OC)=C(OC)C=C3CCN2C)C=C1;
	InChI InChI=1S/C20H24ClNO2/c1-22-11-10-15-12-19(23-2)20(24-3)13-17(15)18(22)9-6-14-4-7-16(21)8-5-14/h4-5,7-8,12-13,18H,6,9-11H2,1-3H3 ; Key:YBCPYHQFUMNOJG-UHFFFAOYSA-N ;
	(verify)

Methopholine is an opioid analgesic 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 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Methopholine tablets were marketed in the United States under the brand name of Versidyne,^[6] but the drug was withdrawn from the market in 1965 due to the occurrence of ophthalmic side-effects and the discovery that it could produce corneal opacities in dogs.^[7]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Analogues where the 4'-chloro group has been replaced by other groups have also been tested, the fluoro derivative being slightly more potent than chloro, and the nitro derivative being most potent of all, with the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]

References

^ US patent 3067203, "Tetrahydroisoquinoline Derivatives", issued 1962-12-04, assigned to Hoffmann-La Roche
^ 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.
^ 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.
^ Cass, L. J.; Frederik, W. S. (1963). "Methopholine, A New Analgesic Agent". The American Journal of the Medical Sciences. 246: 550–557. PMID 14082642.
^ Sciorelli, G. (1967). "Plasma Levels and Renal Excretion of Unchanged Methopholine in Man". Experientia. 23 (11): 934–936. doi:10.1007/bf02136231. PMID 6057015.
^ 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>
^ Federal Register, March 27, 1965 (30 FR 4083).
^ Casy, A. F.; Parfitt, R. Y. (1986). 0-306-42130-5 Opioid Analgesics, Chemistry and Receptors. New York: Plenum Press. p. 390. ISBN 0-306-42130-5. {{cite book}}: Check |url= value (help)CS1 maint: multiple names: authors list (link)
^ 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.

[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.

[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.

[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.

[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.

[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). 0-306-42130-5 Opioid Analgesics, Chemistry and Receptors. New York: Plenum Press. p. 390. ISBN 0-306-42130-5. {{cite book}}: Check |url= value (help)CS1 maint: multiple names: authors list (link)

[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.

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