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Inhibition of monoamine oxidase by selected phenylalkylcaffeine analogues.
J Pharm Pharmacol. 2014 May; 66(5):677-87.JP

Abstract

OBJECTIVES

Caffeine represents a useful scaffold for the design of monoamine oxidase (MAO) type B inhibitors. Specifically, substitution on the C8 position yields structures which are high-potency MAO-B inhibitors. To explore the structure-activity relationships of MAO-B inhibition by caffeine-derived compounds, this study examines the MAO inhibitory properties of a series of phenylalkylcaffeine analogues.

METHODS

Employing the recombinant human enzymes, the potencies (IC50 values) by which the caffeine analogues inhibit MAO-A and MAO-B were measured. The reversibility of inhibition of a selected inhibitor was determined by measuring the recovery of enzyme activity after dilution and dialysis of enzyme-inhibitor mixtures.

KEY FINDINGS

The results document that the phenylalkylcaffeine analogues are reversible and selective MAO-B inhibitors with a competitive mode of inhibition. The most potent analogue, 8-(7-phenylheptyl)caffeine, exhibits IC50 values for the inhibition of MAO-A and MAO-B of 3.01 μm and 0.086 μm, respectively. Increasing the length of the alkyl side chain leads to enhanced MAO-A and MAO-B inhibitory potency while introduction of a carbonyl group reduces MAO-B inhibitory potency.

CONCLUSIONS

Phenylalkylcaffeines represent a new class of high-potency MAO-B inhibitors with the longer alkyl side chains yielding enhanced inhibitory activity. Such compounds may represent useful leads for the development of anti-parkinsonian therapies.

Authors+Show Affiliations

Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24313346

Citation

Petzer, Anél, et al. "Inhibition of Monoamine Oxidase By Selected Phenylalkylcaffeine Analogues." The Journal of Pharmacy and Pharmacology, vol. 66, no. 5, 2014, pp. 677-87.
Petzer A, Grobler P, Bergh JJ, et al. Inhibition of monoamine oxidase by selected phenylalkylcaffeine analogues. J Pharm Pharmacol. 2014;66(5):677-87.
Petzer, A., Grobler, P., Bergh, J. J., & Petzer, J. P. (2014). Inhibition of monoamine oxidase by selected phenylalkylcaffeine analogues. The Journal of Pharmacy and Pharmacology, 66(5), 677-87. https://doi.org/10.1111/jphp.12193
Petzer A, et al. Inhibition of Monoamine Oxidase By Selected Phenylalkylcaffeine Analogues. J Pharm Pharmacol. 2014;66(5):677-87. PubMed PMID: 24313346.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of monoamine oxidase by selected phenylalkylcaffeine analogues. AU - Petzer,Anél, AU - Grobler,Paul, AU - Bergh,Jacobus J, AU - Petzer,Jacobus P, Y1 - 2013/12/09/ PY - 2013/06/26/received PY - 2013/10/30/accepted PY - 2013/12/10/entrez PY - 2013/12/10/pubmed PY - 2014/12/15/medline KW - caffeine KW - competitive KW - monoamine oxidase KW - reversible inhibition KW - structure-activity relationship SP - 677 EP - 87 JF - The Journal of pharmacy and pharmacology JO - J Pharm Pharmacol VL - 66 IS - 5 N2 - OBJECTIVES: Caffeine represents a useful scaffold for the design of monoamine oxidase (MAO) type B inhibitors. Specifically, substitution on the C8 position yields structures which are high-potency MAO-B inhibitors. To explore the structure-activity relationships of MAO-B inhibition by caffeine-derived compounds, this study examines the MAO inhibitory properties of a series of phenylalkylcaffeine analogues. METHODS: Employing the recombinant human enzymes, the potencies (IC50 values) by which the caffeine analogues inhibit MAO-A and MAO-B were measured. The reversibility of inhibition of a selected inhibitor was determined by measuring the recovery of enzyme activity after dilution and dialysis of enzyme-inhibitor mixtures. KEY FINDINGS: The results document that the phenylalkylcaffeine analogues are reversible and selective MAO-B inhibitors with a competitive mode of inhibition. The most potent analogue, 8-(7-phenylheptyl)caffeine, exhibits IC50 values for the inhibition of MAO-A and MAO-B of 3.01 μm and 0.086 μm, respectively. Increasing the length of the alkyl side chain leads to enhanced MAO-A and MAO-B inhibitory potency while introduction of a carbonyl group reduces MAO-B inhibitory potency. CONCLUSIONS: Phenylalkylcaffeines represent a new class of high-potency MAO-B inhibitors with the longer alkyl side chains yielding enhanced inhibitory activity. Such compounds may represent useful leads for the development of anti-parkinsonian therapies. SN - 2042-7158 UR - https://www.unboundmedicine.com/medline/citation/24313346/Inhibition_of_monoamine_oxidase_by_selected_phenylalkylcaffeine_analogues_ DB - PRIME DP - Unbound Medicine ER -