N-Substituted Benztropine Analogs: Selective Dopamine Transporter Ligands with a Fast Onset of Action and Minimal Cocaine-Like Behavioral Effects

Abstract

Previous studies suggested that differences between the behavioral effects of cocaine and analogs of benztropine were related to the relatively slow onset of action of the latter compounds. Several N-substituted benztropine analogs with a relatively fast onset of effects were studied to assess whether a fast onset of effects would render the effects more similar to those of cocaine. Only one of the compounds increased locomotor activity, and the increases were modest compared with those of 10 to 20 mg/kg cocaine. In rats trained to discriminate 10 mg/kg cocaine from saline none of the compounds produced more than 40% cocaine-like responds up to 2 h after injection. None of the compounds produced place-conditioning when examined up to 90 min after injection, indicating minimal abuse liability. The compounds had 5.6 to 30 nM affinities at the dopamine transporter (DAT), with uniformly lower affinities at norepinephrine and serotonin transporters (from 490-4600 and 1420 -7350 nM, respectively). Affinities at muscarinic M 1 receptors were from 100-to 300-fold lower than DAT affinities, suggesting minimal contribution of those sites to the behavioral effects of the compounds. Affinities at histaminic H 1 sites were from 11-to 43-fold lower than those for the DAT. The compounds also had affinity for sigma, 5-hydroxytryptamine 1 (5-HT 1 ) , and 5-HT 2 receptors that may have contributed to their behavioral effects. Together, the results indicate that a slow onset of action is not a necessary condition for reduced cocaine-like effects of atypical DAT ligands and suggest several mechanisms that may contribute to the reduced cocaine-like efficacy of these compounds.

2-Substituted 3 -Aryltropane Cocaine Analogs Produce Atypical Effects without Inducing Inward-Facing Dopamine Transporter Conformations

“…Likewise, muscarinic M 2 sites seem improbable, as the BZT-derived atypical DAT inhibitors have a wide variety of reported activity at this site. Notably, the N-substituted BZT analog GA-299 had little cocaine-like activity and lacked affinity for the M 2 muscarinic site (Li et al, 2011). Previous studies have also found inconsistencies in affinities at 5-HT 1 binding sites among N-substituted BZT analogs Li et al, 2011).…”

“…For example, the D 3 R affinity of LX-20, which did not stimulate locomotor activity, was greater than that for LX-19, which did stimulate activity, and greater than its affinity for the DAT, suggesting a role for D 3 Rs in the atypical effects of LX-20. However, Li et al (2011) examined a group of BZT analogs that were considered atypical DAT ligands. Within that group, the compound that was most like cocaine, JHW013, had the greatest affinity for D 3 Rs.…”

“…More recently, it has been suggested that compounds with sigma receptor (sR) antagonist effects along with their affinity for the DAT will exhibit atypical DAT inhibitory effects similar to BZT . A number of previous studies indicated that sR antagonists can block several effects of cocaine, including locomotor stimulation, sensitization, and place conditioning (see review by Katz et al, 2011), and it is noteworthy that BZT analogs also have affinity for sRs Li et al, 2011).…”

CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction

“…It is well-documented that cocaine's rapid onset of action contributes to its highly-rewarding efficacy and addictive potential (Busto and Sellers, 1986;Kimmel et al, 2008;Kimmel et al, 2007), although not all studies support this view (Li et al, 2011). In rodents, different rates of cocaine delivery affect its addictive liability-drugs reaching the brain rapidly are more addictive than those that reach the brain slowly (Oldendorf, 1992;Samaha and Robinson, 2005;Wakabayashi et al, 2010).…”

Cocaine Antagonists; Studies on Cocaine Self-Administration

“…Thus the slower association rates with DAT might result in a cocaine-antagonist action. However, a study introduced several atypical dopamine uptake inhibitors with fast association rates with DAT in mice [17]. Therefore, it appears that the slower association rates with DAT are not essential for induction of a cocaine-antagonist action, either.…”