Catechol-O-methyl transferase inhibition and potentiation of epinephrine responses by desmethylpapaverine

Burba, John V.; Murnaghan, Maurice F.

doi:10.1016/0006-2952(65)90101-2

Cited by 23 publications

(6 citation statements)

References 7 publications

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“…Whether inhibition is irreversible or involves covalent binding remain to be determined. To our knowledge, no literature exists on the effects of 6,7-dihydroxy DIQs on COMT, but inhibition by the complex 6,7,3',4-tetrahydroxy-isoquinoline alkaloid, papaveroline, was noted by Burba and Murnaghan (1965). Papaveroline's mode of inhibition may be similar to that which we propose for the DIQs in this study, via a quinctidal tautomer.…”

Section: Discussionsupporting

confidence: 64%

Inhibition of Catechol‐O‐Methyltransferase by 6,7‐Dihydroxy‐3,4‐Dihydroisoquinolines Related to Dopamine: Demonstration Using Liquid Chromatography and a Novel Substrate for O‐Methylation

Cheng

Origitano

Collins

1987

Journal of Neurochemistry

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We report that 6,7-dihydroxy-3,4-dihydroisoquinolines related to dopamine are potent inhibitors of catechol-O-methyltransferase (COMT), but are not apparent substrates for the enzyme in vitro or in vivo. Three dihydroxy (catecholic) dihydroisoquinolines, including the 1-benzyl (DesDHP) and the 1-methyl (DSAL) analogs, were found to inhibit COMT activity in rat liver supernatant more effectively than the well-known inhibitor, tropolone. Inhibition of O-methylation was uncompetitive with substrate, and O-methylated products of the catecholic dihydroisoquinolines were undetectable. For these in vitro studies, a facile liquid chromatographic assay was developed utilizing as a site-specific substrate, 1-methyl-6,7-dihydroxy-tetrahydroisoquinoline-1-carboxylate (salsolinol-1-carboxylate). This catechol produces only one phenolic product isomer when incubated with liver supernatant and S-adenosylmethionine. Following central injection of DSAL in rats, inhibition of brain COMT in vivo was indicated by the reduced brain levels of homovanillic acid, but not of 3,4-dihydroxyphenylacetic acid. Furthermore, O-methylated DSAL metabolites could not be detected in brain by liquid or gas chromatography. We suggest that 6,7-dihydroxy-dihydroisoquinolines are "nonmethylatable" COMT inhibitors because they exist as quinoidal tautomers resembling pyridones or tropolones rather than as catechols. Quinoid formation is supported by the fluorescence and ultraviolet spectra for DSAL and its O-methyl derivatives. The experiments reveal a new class of COMT inhibitors that may be of pharmacological and mechanistic value. Additionally, 3,4-dihydroisoquinolines could arise endogenously via oxidation of the 1,2,3,4-tetrahydroisoquinolines which are ingested or produced from cellular catecholamine condensations. However, it is unlikely that dihydroisoquinoline (e.g., DSAL) concentrations necessary to inhibit COMT significantly would be attained via endogenous pathways.

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Section: Discussionsupporting

confidence: 64%

Inhibition of Catechol‐O‐Methyltransferase by 6,7‐Dihydroxy‐3,4‐Dihydroisoquinolines Related to Dopamine: Demonstration Using Liquid Chromatography and a Novel Substrate for O‐Methylation

Cheng

Origitano

Collins

1987

Journal of Neurochemistry

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“…Prior art has shown that papaverine (1) can be O-demethylated partially to the diphenol 6 by refluxing concentrated HC12 and completely to the tetraphenol papaveroline (8) by refluxing 48% HBr. 3 In connection with our interest in the partial O demethylation of polymethoxylated alkaloids,4 we investigated the acidcatalyzed ether cleavage of 1 in more detail.…”

Section: Methodsmentioning

confidence: 99%

Isolation and structure elucidation of oxoxylopine, a new oxoaporphine alkaloid from Stephania abyssinica

Kupchan¹,

Suffness²,

Gordon³

1970

J. Org. Chem.

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llp-acetate, if present, is retained, as shown by conversion of prednisolone 1l117,21-triacetate (3) into 16,17-anhydroprednisolone 1l121-diacetate ( 6 ) , a new compound. The method is also applicable in the 4-en-%one series, and cortisol 17,al-diacetate (4) gave 16,17anhydrocortisol 21-acetate (7). 0 II 0 II CHZOCCHS CH,O&H~ I I c=o c=o 1, A'; R1 = H R, = O=CCH3 2, A'; R1 = H; Rz = O=C(CHJ4CH3 3, A'; Rl = R, = O=CCH, 5, A'; R1 = H 6, A'; R1 = O=CCH, 7,R1=H 4, RI = H R, O=CCH3 0 II CH,OH CH,&CH,Sodium acetate was not so effective as potassium acetate. Sodium formate, calcium carbonate, and calcium acetate in dimethylformamide failed. Potassium acetate in dimethyl sulfoxide and simple pyrolysis were also ineffective.The 17a-acylates are conveniently prepared through the 17a,21 ortho estersS by heating the ortho ester at 45-50' with oxalic acid-water-methanol for 5 min. However, a major weakness of this reported method is formation of the isomeric 17-hydroxy-21-acylate. Gardi, et a l l 3 attribute formation of the isomer to acyl migration from the 17 to the 21 position after cleavage of the ortho ester. We have found that hydrolysis can be effected in a pH 3 phthalate buffer without acyl migration, even on prolonged exposure. Thus hydrolysis of prednisolone 17,21-orthoacetate (8), with pH 3 phthalate buffer in aqueous methanol was complete in 8 hr a t 25". The ratio of 17a-acetate to 21acetate (9 to 10) was estimated to be 9: 1 by thin layer chromatography. The ratio did not change in an additional 64 hr. Using the oxalic acid-aqueous methanol procedure the isomer ratio was 8 : 2 after 5 min of reaction. Experimental SectionAll melting points were taken in open-end glass capillary tubes and are uncorrected. Thin layer chromatograms were visualized by charring, after spraying with sulfuric acid. 1,4,16-Pregnatriene-1 lp-,2 l-diol-3,2O-dione 2 1-Acetate (16,17-Anhydroprednisolone 21-Acetate, 5). A. F r o m 1,4-Pregnadiene-1 lp, 17a,21-triol-3,20-dione 17,21-Diacetate (l).-A mixture of 1 (21 g, 0.0472 mol), anhydrous potassium acetate (10.5 g, 1.07 mol), and dimethylformamide (140 ml) was stirred at 105" for 7.5 hr in an atmosphere of nitrogen. After cooling to 25', the mixture was poured into ice water (1.2 1.) with stirring. After 15 min of stirring, the precipitated solid was collected by filtra-R. Gardi, R. Vitali, and A. Erooli, Gazs. Chim. Ital., 98, 413 (1963). (4) R . Gardi, R. Vitali, and A. Erooli, ibid., 98, 431 (1963). tion, washed with water, and dried to constant weight in vacuo. The yield of 16,17-anhydroprednisolone 21-acetate (5) was 16.8 g (92.8%), mp 197-200', uv max (MeOH) 242 mp (e 23,100), indicating 97% purity. Tlc using either chloroform-acetone (7: 3) or ethyl ether-benzene (9:l) showed only a single spot. Recrystallization from isopropyl alcohol (81.2% recovery) raised the melting point to 205-207' (lit.6 mp 208-209'), uv max (MeOH) 242 mp ( E 23,800). Anal. Calcd for CtaHzsOs: C, 71.85; H, 7.34. Found: C, 71.86; H, 7.25. o m l,4-Pregnadiene-llp,17a,2l-triol-3,20-dione-l7caproate 2 1-Acetate...

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“…Apparently, O-methyltransferase is an extraneuronal enzyme (AXEL-ROD, 1966;HUGHES et aI., 1969;KALSMER and NICKERSON, 1969) BOOTH et aI., 1959) are substrates for catechol-O-methyltransferase; and some of the latter compounds, such as pyrogallol, have been used as enzyme inhibitors (AXELROD and LAROCHE, 1956;BACQ et aI., 1959;CROUT et aI., 1960). Other O-methyltransferase inhibitors have been proposed, such as tropolone derivatives (BELLEAU and BURBA, 1961;MAVRIDES et aI., 1963), desmethylpapaverine (BURBA andMURNAGHAN, 1964) and some O-methylated trihydroxybenzene derivatives (NmODEJEVIC et aI., 1970) ( Table 7). …”

Section: F M·o·methylation: Catechol·o·methyltransferasementioning

confidence: 98%

False Transmitters as Antihypertensive Agents

Porter¹,

Torchiana²,

Stone³

1977

Antihypertensive Agents

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Catechol-O-methyl transferase inhibition and potentiation of epinephrine responses by desmethylpapaverine

Cited by 23 publications

References 7 publications

Inhibition of Catechol‐O‐Methyltransferase by 6,7‐Dihydroxy‐3,4‐Dihydroisoquinolines Related to Dopamine: Demonstration Using Liquid Chromatography and a Novel Substrate for O‐Methylation

Inhibition of Catechol‐O‐Methyltransferase by 6,7‐Dihydroxy‐3,4‐Dihydroisoquinolines Related to Dopamine: Demonstration Using Liquid Chromatography and a Novel Substrate for O‐Methylation

Isolation and structure elucidation of oxoxylopine, a new oxoaporphine alkaloid from Stephania abyssinica

False Transmitters as Antihypertensive Agents

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