Structure−Activity Relationships at Monoamine Transporters and Muscarinic Receptors for N-Substituted-3α-(3‘-chloro-, 4‘-chloro-, and 4‘,4‘ ‘-dichloro-substituted-diphenyl)methoxytropanes

Abstract

The design, synthesis, and evaluation of 3alpha-(diphenylmethoxy)tropane (benztropine) analogues have provided potent and selective probes for the dopamine transporter. Structure-activity relationships (SARs) have been developed that contrast with those described for cocaine, despite significant structural similarity. Furthermore, behavioral evaluation of many of the benztropine analogues in animal models of cocaine abuse has suggested that these two classes of tropane-based dopamine uptake inhibitors have distinct pharmacological profiles. In general, the benztropine analogues do not demonstrate efficacious locomotor stimulation in mice, do not fully substitute for a cocaine discriminative stimulus, and are not appreciably self-administered in rhesus monkeys. These compounds are generally more potent than cocaine as dopamine uptake inhibitors in vitro, although their actions in vivo are not consistent with this action. These observations suggest that differing binding profiles at the serotonin and norepinephrine transporters as well as at muscarinic receptors might have significant impact on the pharmacological actions of these compounds. In addition, by varying the structures of the parent compounds and thereby modifying their physical properties, pharmacokinetics as well as pharmacodynamics will be directly affected. Therefore, in an attempt to systematically evaluate the impact of chemical modification on these actions, a series of N-substituted (H, CH3, allyl, benzyl, propylphenyl, and butylphenyl) analogues of 3'-chloro-, 4'-chloro-, and 4,4''-dichloro-3alpha-(diphenylmethoxy)tropanes were synthesized. These compounds were evaluated for displacement, in rat tissue, of [3H]WIN 35,428 from the dopamine transporter, [3H]citalopram from the serotonin transporter, [3H]nisoxetine from the norepinephrine transporter, and [3H]pirenzepine from muscarinic m1 receptors. SARs were developed and compared to a series of N-substituted-3alpha-(bis-4'-fluorophenyl)methoxytropanes. The present SARs followed previously reported studies with the single exception of the N-butylphenyl substituent, which did not provide the high affinity binding in any of these three sets of analogues, as it did in the 4',4''-difluoro series. X-ray crystallographic analyses of the three parent ligands (1a, 2a, and 3a) were compared to that of 3alpha-(bis-4'-fluorophenyl)methoxytropane which provided supportive evidence toward the proposal that the combination of steric bulk in both the 3-position and the N-substituent, in this class of compounds, is not optimal for binding at the dopamine transporter. These studies provide binding profile data that can now be used to correlate with future behavioral analyses of these compounds and may provide insight into the kind of binding profile that might be targeted as a potential treatment for cocaine abuse.

Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction

“…When the diphenyl ether substituents increased in steric bulk (e.g. 4′,4″-di Cl) N-substitution resulted in further decreases in DAT affinity [78]. However, a notable separation of DAT from muscarinic M1 receptor binding was achieved, with several analogues in this series having > 100-fold selectivity for DAT [77,79,80].…”

Probes for the dopamine transporter: New leads toward a cocaine‐abuse therapeutic—A focus on analogues of benztropine and rimcazole

“…37 An extension of this investigation into optimal N-substitution with varying substitutions on the diphenyl ether have also recently been described. 38 The 3D-QSAR models have been further refined by inclusion of additional structural data ( Fig. 1) These modeling studies showed that for the benztropine series of compounds, the steric interactions along with the electrostatic contributions guided the binding affinity to the DAT.…”

“…In the benztropine series, replacement of the N-methyl group of several halogenated aryl-ring substituted compounds with a propylphenyl group served to decrease binding affinity slightly (K i ¼ 40-160 nM). 32,38 Whereas, in the 4 0 ,4 00 -diF-BZT series, optimal DAT binding affinity was achieved with the N-4 00 -phenyl-n-butyl substituent (43). 32 The Nbenzyl analog was less active (64; K i ¼ 82 nM).…”

N-8-Substituted benztropinamine analogs as selective dopamine transporter ligands

“…[12][13][14][15] Furthermore, the SAR of analogs bearing different substituents on the N-8 nitrogen have been explored. [16][17][18][19] In continuation of the efforts to explore the SAR of BZT analogs, this report examines the isosteric replacement of the benzhydrol ether moiety by a benzhydryl amino group. If such a modification is tolerated at the DAT, it is expected that, compared to their corresponding BZT analogs, the resulting benztropinamine derivatives 4a-m might be more chemically stable and the water solubility might be improved.…”

“…As with 4a, the M1 over DAT selectivity was reduced compared to the corresponding ether derivatives. Only the derivative 4d, with a 3,4-dichloro substitution on both phenyl rings, 18 Binding data were analyzed as described in Table 1. has a somewhat higher binding affinity at the DAT (2-fold) and a higher DAT over M1 selectivity than 4a. However, with 4d DAT selectivity over NET was reduced by 3-fold.…”