Unsaturated heterocyclic amines as potent time-dependent inhibitors of dopamine .beta.-hydroxylase

Bargar, Thomas M.; Broersma, Robert J.; Creemer, Lawrence C.; McCarthy, James R.; Hornsperger, Jean Marie; Palfreyman, Michael G.; Wagner, Joseph; Jung, Michael J.

doi:10.1021/jm00153a002

Cited by 39 publications

(14 citation statements)

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“…There has been increasing interest in the design of substrate analogues and inhibitors for DBM. Several groups have recognized the attractiveness of DBM as a target point for modulation of catecholamine concentrations (May et al, 1981a;Herman et al, 1983;Padgette et al, 1984b;Bargar et al, 1986;Kruse et al, 1986). The pharmacological potential ofsubstrate analogues capable of competing with dopamine for DBM oxygenation and thereby diluting noradrenaline concentrations presynaptically, and of inhibitors that would lower noradrenaline concentrations directly, has become quite clear.…”

Section: Dbm Inhibition By 4-homebi and 4-hobpmentioning

confidence: 99%

“…In addition, DBM-catalysed oxidative ketonization of a-halophenethylamines has been reported by Klinman and co-workers (Klinman & Krueger, 1982;Mangold & Klinman, 1984), and alkyne oxidation has been reported by both us (Padgette et al, 1985a) and Villafranca and co-workers (Colombo et al, 1984a). More recently, Bargar et al (1986) have shown that the phenyl ring of the substrate analogues can be replaced by heteroaromatics such as thienyl and furanyl groups.…”

Section: Introductionmentioning

confidence: 99%

“…There have been a number of reports of sympathomimetic activity, cardiotonic effects and antihypertensive activity for substituted phenylalkyl-imidazoles and -imidazolines (Tuttle et al, 1975;Lucas et al, 1983;Machin et al, 1984;Hamada et al, 1985). We therefore turned our attention to the interaction of phenylalkyl heterocycles with DBM, since there has been increasing interest in this enzyme as a target for pro-drugs or inhibitors designed as possible modulators of adrenergic outflow (May et al, 1981a;Herman et al, 1983;Mangold & Klinman, 1984;Bargar et al, 1986;Kruse et al, 1986). In the present paper we report on the Abbreviations used: DBM, dopamine ,B-mono-oxygenase; g.c., gas chromatography; BI, l-benzylimidazole; 4-HOBI, 1-(4-hydroxybenzyl)imidazole; 3,4-DiHOBI, 1-(3,4-dihydroxybenzyl)imidazole; 4-HOMeBI, 1-(4-hydroxybenzyl)-2-methylimidazole; PEI, 2-phenethylimidazole; 4-HOBP, 1-(4-hydroxybenzyl)pyrazole; 4-HOBA, 4-hydroxybenzaldehyde.…”

Section: Introductionmentioning

confidence: 99%

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Interaction of dopamine β-mono-oxygenase with substituted imidazoles and pyrazoles. Catalysis and inhibition

Sirimanne¹,

Herman²,

May³

1987

Biochemical Journal

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The interaction of dopamine beta-mono-oxygenase (DBM) with substrate analogues possessing either imidazole or pyrazole functionalities at the alkyl chain terminus was investigated. 1-(4-Hydroxybenzyl)imidazole (4-HOBI) is an active substrate for DBM, and it exhibits the expected ascorbate- and fumarate-dependencies and normal kinetic behaviour at concentrations up to 10 mM. 4-Hydroxybenzaldehyde was identified as the product formed from 4-HOBI on the basis of h.p.l.c. and g.c.-m.s. analysis, and its formation exhibits the expected 1:1 stoichiometry with O2 consumption. The 4-HOBI/DBM reaction is kinetically comparable with other DBM activities, and 4-HOBI is the first substrate analogue yet reported that exhibits substantial activity though lacking a terminal amino group. Introduction of a methyl substituent at the 2-position of the imidazole ring abolishes substrate activity, probably through a steric effect. 1-(4-Hydroxybenzyl)pyrazole, where imidazole is replaced by the isomeric pyrazole moiety, is a potent DBM inhibitor, and not a substrate. These results represent the first report of an active heterocyclic substrate or inhibitor for this enzyme, and establish the basis for the design of new classes of DBM substrates and inhibitors.

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Section: Dbm Inhibition By 4-homebi and 4-hobpmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Interaction of dopamine β-mono-oxygenase with substituted imidazoles and pyrazoles. Catalysis and inhibition

Sirimanne¹,

Herman²,

May³

1987

Biochemical Journal

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“…We have also shown that DBM catalyses aromatization of 1-(2-aminoethyl)-1,4-cyclohexadiene (Wimalasena and May, 1989), which represents a redirection of the specificity of this enzyme. A number of substrate analogues have been shown to undergo benzylic methylene oxygenation (Baldini and Villafranca, 1980;Villafranca, 1985, 1986;Kruse et al, 1986;Bargar et al, 1986;Ross et al, 1987).…”

Section: Introductionmentioning

confidence: 99%

Interaction of non-conjugated olefinic substrate analogues with dopamine β-monooxygenase: catalysis and mechanism-based inhibition

Sirimanne

May

1995

Biochemical Journal

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The reaction of dopamine beta-monooxygenase (DBM; EC 1.14.17.1) with the prototypical non-conjugated olefinic substrate, 2-(1-cyclohexenyl)ethylamine (CyHEA) [see Sirimanne and May (1988) J. Am. Chem. Soc. 110, 7560-7561], was characterized. CyHEA undergoes facile DBM-catalysed allylic hydroxylation to form (R)-2-amino-1-(1-cyclohexenyl)ethanol (CyHEA-OH) without detectable epoxidation or allylic hydroxylation to form (R)-2-amino-1-(1-cyclohexenyl)ethanol (CyHEA-OH) without detectable epoxidation or allylic rearrangement, and with stereochemistry consistent with that of DBM-catalysed benzylic hydroxylation and sulphoxidation. The kcat. of 90 s-1 for CyHEA oxygenation is about 75% of the kcat. for tyramine, the substrate commonly used in assays of DBM activity. DBM-catalysed oxygenation of CyHEA also results in mechanism-based inactivation of DBM, with the inactivation reaction yielding kinact. = 0.3 min-1 at pH 5.0 and 37 degrees C, and a partition ratio of 16,000. Although both CyHEA turnover and inactivation exhibit normal kinetics, CyHEA processing also results in gradual depletion of copper from DBM; however, mechanism-based irreversible DBM inactivation occurs independent of this copper depletion when sufficient copper is present in the assay solution. A likely mechanism for turnover-dependent DBM inactivation by CyHEA involves initial abstraction of an allylic hydrogen to form a resonance-stabilized allylic radical, which can then either partition to product or undergo attack by an active-site residue. Acyclic, non-conjugated olefinic analogues exhibit diminished substrate activity toward DBM. Thus, kcat. for oxygenation of cis-2-hexenylamine, which also produces only allylic alcohol product, is only 14% of that for CyHEA. Similarly, kinact./KI for turnover-dependent inactivation by the acyclic olefin 2-aminomethyl-1-pentene is more than an order of magnitude smaller than that for benzylic olefins. Our results establish that DBM catalyses allylic oxygenation of a number of non-conjugated olefinic substrate analogues with neither epoxidation nor allylic rearrangement occurring. The absence of epoxide products from non-conjugated olefinic substrates implies an inability of the activated copper-oxygen species of DBM to effect radical cation formation from a non-conjugated olefinic moiety. The striking contrast between DBM and cytochrome P-450, which carries out both epoxidation and allylic oxidation with non-conjugated olefinic substrates, is probably a reflection of the differences in redox potential of the activated oxygen species operative for these two enzymes.

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“…To date, only one class of mechanism-based inhibitors, some heterocyclic allylamines, appear to fulfill this criterion. 14 In this paper we describe a simple ethynyl-substituted tyramine that is an effective mechanism-based inhibitor of DBH; it binds enzyme in the micromolar range, nearly 100-fold more…”

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confidence: 99%

New human renin inhibitors containing an unnatural amino acid, norstatine

Iizuka

Kamijo²,

Kubota³

et al. 1988

J. Med. Chem.

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A large number of renin inhibitors have been investigated as targets of antihypertensive drugs.1 2345678"9 However, most of them were peptide compounds and, hence, thought to be unsuitable for oral administration because of their proteolytic lability and poor absorption in the digestive canal. We report here an orally active renin inhibitor KRI-1230 (compound 9 in Table I) containing norstatine [norSta: (2R,3S)-3-amino-2-hydroxy-5-methylhexanoic acid], an unnatural amino acid.We initiated a study on renin inhibitors in order to analyze the mode of interaction between human renin and its substrate. Because the X-ray structure of human renin has not been determined, we deduced10 a tertiary structure of the enzyme based upon the assumption11 that the overall folding of human renin is very similar to that of penicillopepsin.12 The modeling of human renin was carried out(1)

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Unsaturated heterocyclic amines as potent time-dependent inhibitors of dopamine .beta.-hydroxylase

Cited by 39 publications

References 0 publications

Interaction of dopamine β-mono-oxygenase with substituted imidazoles and pyrazoles. Catalysis and inhibition

Interaction of dopamine β-mono-oxygenase with substituted imidazoles and pyrazoles. Catalysis and inhibition

Interaction of non-conjugated olefinic substrate analogues with dopamine β-monooxygenase: catalysis and mechanism-based inhibition

New human renin inhibitors containing an unnatural amino acid, norstatine

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