The Inhibition of Monoamine Oxidase by Phenformin and Pentamidine

M. Barkhuizen; A. Petzer; J. P. Petzer

doi:10.1055/s-0033-1361129

Drug Research, Table of Contents

Drug Res (Stuttg) 2014; 64(09): 454-461
DOI: 10.1055/s-0033-1361129

Original Article

The Inhibition of Monoamine Oxidase by Phenformin and Pentamidine

M. Barkhuizen

¹Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom, South Africa

,

A. Petzer

²Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Potchefstroom, South Africa

,

J. P. Petzer

¹Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom, South Africa

› Author Affiliations

Abstract

A computational study has suggested that phenformin, an oral hypoglycaemic drug, may bind to the active sites of the monoamine oxidase (MAO) A and B enzymes. The present study therefore investigates the MAO inhibitory properties of phenformin. Pentamidine, a structurally related diamidine compound, has previously been reported to be a MAO inhibitor and was included in this study as a reference compound. Using recombinant human MAO-A and MAO-B, this study finds that phenformin acts as a moderately potent MAO-A selective inhibitor with an IC₅₀ value of 41 µM. Pentamidine, on the other hand, potently inhibits both MAO-A and MAO-B with IC₅₀ values of 0.61 μM and 0.22 μM, respectively. An examination of the recoveries of the enzymatic activities after dilution and dialysis of the enzyme-inhibitor complexes shows that both compounds interact reversibly with the MAO enzymes. A kinetic analysis suggests that pentamidine acts as a competitive inhibitor with estimated K_i values of 0.41 μM and 0.22 μM for the inhibition of MAO-A and MAO-B, respectively. Phenformin also exhibited a competitive mode of MAO-A inhibition with an estimated Ki value of 65 µM. This study concludes that biguanide and amidine functional groups are most likely important structural features for the inhibition of the MAOs by phenformin and pentamidine, and compounds containing these and closely related functional groups should be considered as potential MAO inhibitors. Furthermore, the biguanide and amidine functional groups may act as useful moieties in the future design of MAO inhibitors.

Key words

biguanides - amidines - guanidine - phenformin - pentamidine - inhibition - monoamine oxidase

Full Text

References

References
1 Xian M, Li X, Tang X et al. N-hydroxyl derivatives of guanidine based drugs as enzymatic NO donors. Bioorg Med Chem Lett 2001; 11: 2377-2380
2 Berlinck RG. Natural guanidine derivatives. Nat Prod Rep 1996; 13: 377-409
3 Berlinck RG, Burtoloso AC, Kossuga MH. The chemistry and biology of organic guanidine derivatives. Nat Prod Rep 2008; 25: 919-954
4 Malinow SH. Comparison of guanadrel and guanethidine efficacy and side effects. Clin Ther 1983; 5: 284-289
5 Giroud C, Moreau M, Mattioli TA et al. Role of arginine guanidinium moiety in nitric-oxide synthase mechanism of oxygen activation. J Biol Chem 2010; 285: 7233-7245
6 Guthrie RM. Evolving therapeutic options for type 2 diabetes mellitus: an overview. Postgrad Med 2012; 124: 82-89
7 Fimognari FL, Pastorelli R, Incalzi RA. Phenformin-induced lactic acidosis in an older diabetic patient: a recurrent drama (phenformin and lactic acidosis). Diabetes Care 2006; 29: 950-951
8 Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med 2002; 137: 25-33
9 Aziz Q, Thomas A, Khambra T et al. Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel. Eur J Pharmacol 2010; 634: 26-32
10 Towler MC, Hardie DG. AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res 2007; 100: 328-341
11 Dilman VM, Berstein LM, Zabezhinski MA et al. Inhibition of DMBA-induced carcinogenesis by phenformin in the mammary gland of rats. Arch Geschwulstforsch 1978; 48: 1-8
12 Appleyard MV, Murray KE, Coates PJ et al. Phenformin as prophylaxis and therapy in breast cancer xenografts. Br J Cancer 2012; 106: 1117-1122
13 Evans JM, Donnelly LA, Emslie-Smith AM et al. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005; 330: 1304-1305
14 Wispelwey B, Pearson RD. Pentamidine: a review. Infect Control Hosp Epidemiol 1991; 12: 375-382
15 Blaschko H, Duthie R. The inhibition of amine oxidase by amidines. Biochem J 1945; 39: 347-350
16 Davison AN. The irreversible inhibition of monoamine oxidase in vivo. Arch Biochem Biophys 1958; 77: 368-371
17 Youdim MB, Bakhle YS. Monoamine oxidase: isoforms and inhibitors in Parkinson’s disease and depressive illness. Br J Pharmacol 2006; 147 (Suppl. 01) S287-S296
18 Yamada M, Yasuhara H. Clinical pharmacology of MAO inhibitors: safety and future. Neurotoxicology 2004; 25: 215-221
19 Youdim MB, Edmondson D, Tipton KF. The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci 2006; 7: 295-309
20 Finberg JP, Wang J, Bankiewicz K et al. Increased striatal dopamine production from L-DOPA following selective inhibition of monoamine oxidase B by R(+)-N-propargyl-1-aminoindan (rasagiline) in the monkey. J Neural Transm Suppl 1998; 52: 279-285
21 Da Prada M, Zürcher G, Wüthrich I et al. On tyramine, food, beverages and the reversible MAO inhibitor moclobemide. J Neural Transm Suppl 1988; 26: 31-56
22 Harfenist M, Heuser DJ, Joyner CT et al. Selective inhibitors of monoamine oxidase. 3. Structure-activity relationship of tricyclics bearing imidazoline, oxadiazole, or tetrazole groups. J Med Chem 1996; 39: 1857-1863
23 Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction. Br J Pharmacol 2007; 152: 946-951
24 Stanford SC, Stanford BJ, Gillman PK. Risk of severe serotonin toxicity following co-administration of methylene blue and serotonin reuptake inhibitors: an update on a case report of post-operative delirium. J Psychopharmacol 2010; 24: 1433-1438
25 Soriato G, Focati MP, Brescello R et al. Pharmaceutical preparations of crystalline lazabemide. Patent 2008 WO 2008010794
26 Petzer A, Harvey BH, Wegener G et al. Azure B, a metabolite of methylene blue, is a high-potency, reversible inhibitor of monoamine oxidase. Toxicol Appl Pharmacol 2012; 258: 403-409
27 Novaroli L, Reist M, Favre E et al. Human recombinant monoamine oxidase B as reliable and efficient enzyme source for inhibitor screening. Bioorg Med Chem 2005; 13: 6212-6217
28 Strydom B, Bergh JJ, Petzer JP. The inhibition of monoamine oxidase by 8-(2-phenoxyethoxy)caffeine analogues. Arzneimittelforschung 2012; 62: 513-518
29 Manley-King CI, Bergh JJ, Petzer JP. Inhibition of monoamine oxidase by selected C5- and C6-substituted isatin analogues. Bioorg Med Chem 2011; 19: 261-274
30 Petzer A, Pienaar A, Petzer JP. The Inhibition of Monoamine Oxidase by Esomeprazole. Arzneimittelforschung 2013; 63: 462-467
31 Oates NS, Shah RR, Idle JR et al. Influence of oxidation polymorphism on phenformin kinetics and dynamics. Clin Pharmacol Ther 1983; 34: 827-834
32 Provost JC, Funck-Brentano C, Rovei V et al. Pharmacokinetic and pharmacodynamic interaction between toloxatone, a new reversible monoamine oxidase-A inhibitor, and oral tyramine in healthy subjects. Clin Pharmacol Ther 1992; 52: 384-393
33 Boulton AA. Phenylethylaminergic modulation of catecholaminergic neurotransmission. Prog Neuropsychopharmacol Biol Psychiatry 1991; 15: 139-156
34 Lasbennes F, Sercombe R, Seylaz J. Monoamine oxidase activity in brain microvessels determined using natural and artificial substrates: relevance to the blood-brain barrier. J Cereb Blood Flow Metab 1983; 3: 521-528
35 Finberg JP, Lamensdorf I, Armoni T. Modification of dopamine release by selective inhibitors of MAO-B. Neurobiology (Bp) 2000; 8: 137-142
36 Pae CU, Bodkin JA, Portland KB et al. Safety of selegiline transdermal system in clinical practice: analysis of adverse events from postmarketing exposures. J Clin Psychiatry 2012; 73: 661-668
37 Binda C, Newton-Vinson P, Hubálek F et al. Structure of human monoamine oxidase B, a drug target for the treatment of neurological disorders. Nat Struct Biol 2002; 9: 22-26
38 Binda C, Wang J, Pisani L et al. Structures of human monoamine oxidase B complexes with selective noncovalent inhibitors: safinamide and coumarin analogs. J Med Chem 2007; 50: 5848-5852
39 Hubálek F, Binda C, Khalil A et al. Demonstration of isoleucine 199 as a structural determinant for the selective inhibition of human monoamine oxidase B by specific reversible inhibitors. J Biol Chem 2005; 280: 15761-15766
40 Son SY, Ma J, Kondou Y et al. Structure of human monoamine oxidase A at 2.2-A resolution: the control of opening the entry for substrates/inhibitors. Proc Natl Acad Sci USA 2008; 105: 5739-5744