Highly selective chiral N-substituted 3 alpha-[bis(4 '-fluorophenyl)methoxy]tropane analogues for the dopamine transporter: Synthesis and comparativemolecular field analysis

In a continuing effort to further characterize the role of the dopamine tra nsporter in the pharmacological effects of cocaine, a series of chiral and achiral N-substituted analogues of 3 alpha-[bis(4'-fluorophenyl)methoxy]tro pane (5) has been prepared as potential selective dopamine transporter liga nds. These novel compounds displaced [H-3]WIN 35,428 binding from the dopam ine transporter in rat caudate putamen with K-i values ranging from 13.9 to 477 nM. Previously, it was reported that 5 demonstrated a significantly hi gher affinity for the dopamine transporter than the parent drug, 3 alpha-(d iphenylmethoxy)tropane (3; benztropine). However, 5 remained nonselective o ver muscarinic mi receptors (dopamine transporter, K-i = 11.8 nM; m(1), K-i = 11.6 nM) which could potentially confound the interpretation of behavior al data, for this compound and other members of this series. Thus, signific ant effort has been directed toward developing analogues that retain high a ffinity at the dopamine transporter but have decreased affinity at muscarin ic sites. Recently, it was discovered that by replacing the N-methyl group of 5 with the phenyl-n-butyl substituent (6) retention of high binding affi nity at the dopamine transporter (K-i = 8.51 nM) while decreasing affinity at muscarinic receptors (K-i = 576 nM) was achieved, resulting in 68-fold s electivity. In the present series, a further improvement in the selectivity for the dopamine transporter was accomplished, with the chiral analogue (S )N-(2-amino-3-methyl-n-butyl)-3 alpha-[bis(4'-fluorophenyl)methoxy]tropane( 10b) showing a 136-fold selectivity for the dopamine transporter versus mus carinic mi receptors (K-i = 29.5 nM versus K-i = 4020 nM, respectively). In addition, a comparative molecular field analysis (CoMFA) model was derived to correlate the binding affinities of all the N-substituted 3 alpha-[bis( 4'-fluorophenyl)methoxy]tropane analogues that we have prepared with their 3D-structural features. The best model (q(2) = 0.746) was used to accuratel y predict binding affinities of compounds in the training set and in a test set. The CoMFA coefficient contour plot for this model, which provides a v isual representation of the chemical environment of the binding domain of t he dopamine transporter, can now be used to design and/or predict the bindi ng affinities of novel drugs within this class of dopamine uptake inhibitor s.