Naijue Zhu

7-Ethynylcoumarins: Selective Inhibitors of Human Cytochrome P450s 1A1 and 1A2

To discover new selective mechanism-based P450 inhibitors, eight 7-ethynylcoumarin derivatives were prepared through a facile two-step synthetic route. Cytochrome P450 activity assays indicated that introduction of functional groups in the backbone of coumarin could enhance the inhibition activities toward P450s 1A1 and 1A2, providing good selectivity against P450s 2A6 and 2B1. The most potent product 7-ethynyl-3,4,8-trimethylcoumarin (7ETMC) showed IC(50) values of 0.46 μM and 0.50 μM for P450s 1A1 and 1A2 in the first six minutes, respectively, and did not show any inhibition activity for P450s 2A6 and 2B1 even at the dose of 50 μM. All of the inhibitors except 7-ethynyl-3-methyl-4-phenylcoumarin (7E3M4PC) showed mechanism-based inhibition of P450s 1A1 and 1A2. In order to explain this mechanistic difference in inhibitory activities, X-ray crystallography data were used to study the difference in conformation between 7E3M4PC and the other compounds studied. Docking simulations indicated that the binding orientations and affinities resulted in different behaviors of the inhibitors on P450 1A2. Specifically, 7E3M4PC with its two-plane structure fits into the P450 1A2s active site cavity with an orientation leading to no reactive binding, causing it to act as a competitive inhibitor.

Synthesis and dopamine transporter binding affinities of 3α-benzyl-8-(diarylmethoxyethyl)-8-azabicyclo[3.2,1]octanes

A series of 3alpha-benzyl-8-(diarylmethoxyethyl)-8-azabicyclo[3.2.1]octanes was synthesized and the binding affinities of the compounds were determined at the dopamine transporter. The unsubstituted analogue 7b (K(i)=98nM) was the most potent compound of the series with binding affinity three-times greater than cocaine and only 5-fold less than GBR-12909. The structure-activity data for 7a-f suggests that these compounds may be binding at the dopamine transporter in a similar fashion to GBR 12909.

QSAR and CoMFA Study of Cocaine Analogs: Crystal and Molecular Structure of (–)-Cocaine Hydrochloride and N-Methyl-3β-(p-Fluorophenyl)Tropane-2β-Carboxylic Acid Methyl Ester

A QSAR and CoMFA study including 78 cocaine analogs has been completed. These analogs have varied functional groups on the 2β and 3β positions of the tropane ring and include various stereoisomers. The CoMFA program was used to calculate the steric and electrostatic interaction energies as a probe atom or probe charge interacts with the molecules. Shaded contour maps show regions of the cocaine analogs where an increase in bulky substituents is desirable for increased pharmacological activity. The maps also show that small electronegative substituents on the phenyl ring are favored for enhanced activity. The X-ray crystal structures of (–)-cocaine hydrochloride (1) and N-methyl-3β-(p-fluorophenyl)tropane-2β-carboxylic acid methyl ester (2) are reported. These molecules are mostly rigid except for some rotational flexibility in the orientation of the phenyl and benzoyl functional groups. Crystallographic data: (1) C17H21NO4·HCl, orthorhombic space group P212121, a = 7.622(1)Å, b = 10.285(1)Å, c = 21.428(3)Å, Z = 4, final R = 0.035 for 960 observed reflections (I>3σ(I)). (2) C16H20FNO2, monoclinic space group C2, a = 22.572(7)Å, b = 5.810(1)Å, c = 15.752(4)Å, β = 133.65(2)°, Z = 4, final R = 0.059 for 1511 observed reflections (I>3σ(I)).