Synthesis and Ligand Binding Studies of 4‘-Iodobenzoyl Esters of Tropanes and Piperidines at the Dopamine Transporter

Abstract

Four analogs and two homologs of cocaine, designed as potent cocaine antagonists, were synthesized. The SN2 reaction between ecgonine methyl ester (13) or appropriately substituted piperidinol (19, 21) and appropriately substituted 4-iodobenzoyl chloride gave 4-iodobenzoyl esters of tropanes and piperidines (5-8). 2'-Hydroxycocaine (9) was obtained from 2'-acetoxycocaine (12) by selective transesterification with MeOH saturated with dry HCl gas. 2'-Acetoxycocaine (12) was synthesized from acetylsalicyloyl chloride (23) and ecgonine methyl ester (13). The binding affinities of these compounds were determined at the dopamine transporter for the displacement of [3H]WIN-35428. An iodo group substitution at the 4'-position of cocaine decreased dopamine transporter binding potency, while a hydroxy or acetoxy group at the 2'-position exhibited increased binding potency for the dopamine transporter compared to cocaine (10- and 3.58-fold, respectively). 2'-Hydroxylation also enhanced the bidning potency of 4'-iodococaine (5) by 10-fold. Replacement of the tropane ring with piperidine led to poor binding affinities.

Evaluation of anti-cocaine antibodies and a cocaine vaccine in a rat self-administration model

“…One ramification is that immunization with a cocaine vaccine would be expected to be compatible with other addiction medications as long as the antibodies do not recognize and neutralize the added pharmacological agent. Most medications under development are structurally unrelated to cocaine, although exceptions can be found (Carroll et al 1994;Katz et al 1997;Singh et al 1997). The compatibility of the vaccine with structurally similar and dissimilar treatment medications will be very important to establish, as it may be valuable to adjunctively administer additional medications to reduce cocaine craving, particularly during the immunization period.…”

Synthesis and Preliminary Evaluation of Piperidinyl and Pyrrolidinyl Iodobenzoates as Imaging Agents for Butyrylcholinesterase

“…The product was purified by silica gel chromatography (30:70 MeOH/CH 2 Cl 2 ) to give a white powder (0.5561 g, 54%). Analytical data: MP: 128-130°C (Lit MP=130°C [26] These structures are absent in normal brain (a-c). In normal brain there is a low level of BuChE (a) in the cortex and no β-amyloid plaques (c) while there is relatively intense AChE staining (b).…”

Chemistry and Pharmacology of the Piperidine-Based Analogues of Cocaine. Identification of Potent DAT Inhibitors Lacking the Tropane Skeleton

“…These two compounds, whose structures are shown below, exhibited IC 50 's for displacement of WIN Scheme 2. Synthesis of the Trans-Disubstituted Piperidine Analogues 12 Accordingly, both compounds are less active than cocaine or 4′-iodococaine (IC 50 's reported for cocaine and for 4′-iodococaine are 249 and 2522 nM, respectively). The conclusion was accordingly reached that although the interatomic distances between the nitrogen atom of the piperidine ring and the iodine atom in compounds 16 and 17 are the same as that found in 4′-iodococaine, the lack of conformational rigidity of the piperidines or the adoption of the other chair conformations may lead to poor binding affinity.…”