Abraham Philip

New, potent cocaine analogs: ligand binding and transport studies in rat striatum

Two potent cocaine analogs have been developed that have the highest known affinities for the cocaine binding site in rat striatum. Both 3 beta-(4-chlorophenyl)- (RTI-COC-31) and 3 beta-(4-methylphenyl)-tropane-2-carboxylic acid methyl ester (RTI-COC-32) compete for [3H]WIN 35,428 and [3H]mazindol binding with a IC50 that is 100 times more potent than that of (-) cocaine. Additionally, these compounds inhibit [3H]dopamine uptake with a similar, high potency. These results may lead to the development of high affinity probes for the cocaine binding site.

High potency cocaine analogs: Neurochemical, imaging, and behavioral studies

Recent evidence suggests the behavioral properties of cocaine are related to its ability to inhibit dopamine (DA) reuptake.1.2 Specific binding sites tbr cocaine have been identified with a host of Iqpnds, including [3H]cocaine.3-5 However, the use of [3H]cocaine as a ligand presents many problems, including its low affinity and rapid dissociation rate. While other non-cocaine-like lignds such as GBR 12935, mazindol, and nomifensine overcome the problems of low affinity and rapid dissociation, they present problems of their own. These ligands bind to a single high aflinity site, while cocaine binds to both a high and low affinity site. Furthermore, Madras et af .6 reported that [3H]cocaine was not l l l y displaced by these non-cocaine-like drugs. Thus it appears that in order to correctly identify the molecular structural requirements fbr cocaine binding one must utilize cocaine or cocaine analogs. It was reported by Clarke et af.7 that removal of the ester linkage between the phenyl ring and tropane ring of cocaine (FIG. 1) results in the compound designated WIN 35,065-2. This compound demonstrated a hlgher affinity for the dopamine transporter than cocaine itself. Addition of fluorine to the pm-position of the phenyl ring (WIN 35,428, also designated CET) hrther enhanced potency. Both WIN 35,065-2 and WIN 35,428 have been radioactively labeled and have proven to be superior ligands fbr in vim binding studies when compared to cocaine.6*8

Potent substituted-3β-phenyltropane analogs of cocaine have cocaine-like discriminative stimulus effects

Two novel phenyltropane analogs of cocaine, 3 beta-(4-chlorophenyl) tropane-2 beta-carboxylic acid methyl ester (RTI-COC-31) and 3 beta-(4-methylphenyl) tropane-2 beta-carboxylic acid methyl ester (RTI-COC-32), were evaluated for cocaine-like discriminative stimulus effects in rats. Two groups of rats were trained to discriminate 10 mg/kg cocaine from saline using a standard 2-lever discrimination procedure with correct-lever responding reinforced under a fixed-ratio 20 schedule of food reinforcement. One group of rats was used to evaluate RTI-COC-31 and the unsubstituted-3 beta-phenyltropane reference compound WIN 35,065-2 in substitution tests. Another group of rats was used to evaluate RTI-COC-32. For purposes of comparison, a cocaine dose-effect curve was also determined in each group. Both RTI-COC-31 and RTI-COC-32, as well as WIN 35,065-2, substituted completely for cocaine. RTI-COC-31 was 26.8-fold and RTI-COC-32 was 6-fold more potent than cocaine for producing cocaine-lever responding. The potent cocaine-like effects of the RTI analogs in vivo correspond with their high affinities for a cocaine recognition site on the dopamine transporter, providing further evidence that this site may mediate behavioral effects of cocaine relevant to its abuse.

A cocaine analog and a GBR analog label the same protein in rat striatal membranes

Because some evidence suggests that cocaine and GBR12935 bind to different sites, we utilized photoaffinity probes from both classes of compounds to see if they label the same protein. [125I]RTI-82 a cocaine analog, and [125I]DEEP, a GBR analog, labeled protein(s) showing the same molecular weight, a similar pharmacological profile and a similar sensitivity to neuraminidase.

A concise synthesis of (±)-, (+)-, and (–)-6-methyl-6-azabicyclo[3.2.l]octan-3α-ol

(±)-6-Methyl-6-azabicyclo[3.2.1]octan-3-one (1c) was prepared in three steps from 6-oxabicyclo[3.2.1]oct-3-en-7-one, and stereoselective reduction of (1c) provided (±)-6-methyl-6-azabicyclo[3.2.1]octan-3α-ol (1a); adaptation of the sequence provided the first synthesis of (+)- and (–)-(1a).