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Quantitative structure-activity relationship analysis of inhibitors of the nicotine metabolizing CYP2A6 enzyme.

Journal of medicinal chemistry (2005-01-22)
Minna Rahnasto, Hannu Raunio, Antti Poso, Carsten Wittekindt, Risto O Juvonen
ABSTRACT

The purpose of this study was to develop screening and in silico modeling methods to obtain accurate information on the active center of CYP2A6, a nicotine oxidizing enzyme. The inhibitory potencies of 26 naphthalene and 16 non-naphthalene derivatives were determined for human CYP2A6 and mouse CYP2A5 enzymes. Several comparative molecular field analysis (CoMFA) models were developed to find out what types of steric and electrostatic properties are required for potent inhibitors. The IC(50) values of the tested compounds varied from 0.55 to 35 400 microM for CYP2A6 and from 1 to 1500 microM for CYP2A5. The generated CoMFA models were able to accurately predict the inhibition potencies of an external test set of chemicals. Potent and specific inhibitors of the CYP2A6 enzyme can be used in the future to increase nicotine bioavailability and thus make oral nicotine administration feasible in smoking cessation therapy.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Benzaldehyde, ReagentPlus®, ≥99%
Sigma-Aldrich
p-Anisaldehyde, 98%
Sigma-Aldrich
Naphthalene, 99%
Sigma-Aldrich
Benzaldehyde, purified by redistillation, ≥99.5%
Sigma-Aldrich
(−)-Nicotine, ≥99% (GC), liquid
Sigma-Aldrich
1-Naphthol, ReagentPlus®, ≥99%
Sigma-Aldrich
2-Naphthol, 99%
Sigma-Aldrich
Coumarin, ≥99% (HPLC)
Sigma-Aldrich
p-Tolualdehyde, 97%
Supelco
Naphthalene, analytical standard
Sigma-Aldrich
Phenanthrene, 98%
Sigma-Aldrich
1-Methylnaphthalene, 95%
Supelco
Benzaldehyde, analytical standard
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1,4-Dichlorobenzene, ≥99%
Supelco
(−)-Nicotine, PESTANAL®, analytical standard
Sigma-Aldrich
1-Chloronaphthalene, technical grade
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1,4-Dibromobenzene, 98%
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α-Tetralone, 97%
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Phenethylamine, ≥99%
Supelco
Melting point standard 79-81°C, analytical standard
Sigma-Aldrich
2-Methylnaphthalene (β), 97%
Sigma-Aldrich
Benzaldehyde, puriss. p.a., ≥99.0% (GC)
Supelco
p-Anisaldehyde, analytical standard
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2-Bromonaphthalene, 97%
Sigma-Aldrich
2-Methoxynaphthalene, 99%
Sigma-Aldrich
Naphthalene, suitable for scintillation, ≥99%
Supelco
(−)-Nicotine solution, 1.0 mg/mL, analytical standard, for drug analysis
Sigma-Aldrich
Phenanthrene, sublimed grade, ≥99.5%
Sigma-Aldrich
(−)-Cotinine, ≥98%
Sigma-Aldrich
Benzaldehyde, natural, FCC, FG

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