Hybrid (Bisarylmethoxy)butylpiperazine Analogs as Neurotransmitter Transporter Inhibitors with Activity at Dopamine Receptor Sites as Potential Cocaine Antagonists
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Agents which prevent binding of cocaine to the dopamine transporter (DAT) weakly inhibit the reuptake of DA and act as antagonists at DA/ serotonin (5-HT) receptors might be useful drugs for treating cocaine addiction by assisting cocaine addicts in maintaining abstinence. To determine the structural requirements necessary for this dual activity at DAT and DA/5-HT receptor sites, a series of (bisarylmethoxy)butylpiperazine derivatives was prepared and evaluated in vitro and in vivo. These hybrid ligands were constructed by combining pharmacophores for the DAT and the DA/5-HT receptor. The initial series was evaluated in vitro as DAT and DA/5-HT receptor ligands and selected target compounds were tested in vivo for effects on cocaine-induced hyper-locomotor activity (LMA). Most of the new compounds demonstrated high to moderate affinity (4 to 175 nM) at the DAT. Compound 18exhibited the highest discrimination ratio (DR) of 144. These derivatives displayed modest affinity for and antagonistic activity at D 2 /D 3 DA receptors. Compounds 10 and 18 stimulated LMA whereas compound 16 suppressed the response. Cocaine-induced hyperlocomotion was attenuated by compounds 16 and 18. The results of this study demonstrate that (bisarylmethoxy)butylpiperazine derivatives may be of value in the development of therapeutics for treating cocaine abuse/addiction and in the further pharmacological and biological characterization of the DAT.
Abstract
Agents which prevent binding of cocaine to the dopamine transporter (DAT) weakly inhibit the reuptake of DA and act as antagonists at DA/ serotonin (5-HT) receptors might be useful drugs for treating cocaine addiction by assisting cocaine addicts in maintaining abstinence. To determine the structural requirements necessary for this dual activity at DAT and DA/5-HT receptor sites, a series of (bisarylmethoxy)butylpiperazine derivatives was prepared and evaluated in vitro and in vivo. These hybrid ligands were constructed by combining pharmacophores for the DAT and the DA/5-HT receptor. The initial series was evaluated in vitro as DAT and DA/5-HT receptor ligands and selected target compounds were tested in vivo for effects on cocaine-induced hyper-locomotor activity (LMA). Most of the new compounds demonstrated high to moderate affinity (4 to 175 nM) at the DAT. Compound 18exhibited the highest discrimination ratio (DR) of 144. These derivatives displayed modest affinity for and antagonistic activity at D 2 /D 3 DA receptors. Compounds 10 and 18 stimulated LMA whereas compound 16 suppressed the response. Cocaine-induced hyperlocomotion was attenuated by compounds 16 and 18. The results of this study demonstrate that (bisarylmethoxy)butylpiperazine derivatives may be of value in the development of therapeutics for treating cocaine abuse/addiction and in the further pharmacological and biological characterization of the DAT.
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