QSAR and CoMFA study of cocaine analogs: Crystal and molecular structure of (-)-cocaine hydrochloride and N-methyl-3 beta-(p-fluorophenyl)tropane-2 beta-carboxylic acid methyl ester

A QSAR and CoMFA study including 78 cocaine analogs has been completed. The se analogs have varied functional groups on the 2 beta and 3 beta positions of the tropane ring and include various stereoisomers. The CoMFA program w as used to calculate the steric and electrostatic interaction energies as a probe atom or probe charge interacts with the molecules. Shaded contour ma ps show regions of the cocaine analogs where an increase in bulky substitue nts 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 hydrochlori de (1) and N-methyl-3 beta-(p-fluorophenyl)tropane-2 beta-carboxylic acid m ethyl ester (2) are reported. These molecules are mostly rigid except for s ome rotational flexibility in the orientation of the phenyl and benzoyl fun ctional groups. Crystallographic data: (1) C17H21NO4. HCl, orthorhombic spa ce group P2(1)2(1)2(1), a = 7.622(1)Angstrom, b = 10.285(1) Angstrom, c = 2 1.428(3)Angstrom, Z = 4, final R = 0.035 for 960 observed reflections (I > 3 sigma(I)). (2) C16H20FNO2, monoclinic space group C2, a = 22.572(7)Angstr om, b = 5.810(1)Angstrom, c = 15.752(4)Angstrom, beta = 133.65(2)degrees, Z = 4, final R = 0.059 for 1511 observed reflections (I > 3 sigma(I)).