Identification of stereoselective, high affinity saturable binding sites for cocaine 1 in the mammalian central nervous system (CNS) have been described in both in vitro and in vivo systems.1-10 The CNS pharmacologic activity of cocaine has been shown to be mediated through occupation of a structure specific cocaine receptor.11,12 It is believed that the primary mechanism of action of cocaine is associated with the blockade of CNS biogenic amine uptake systems. Inhibition of the serotonin, dopamine and norepinephrine uptake mechanisms by cocaine have all been reported.13,14 However, the pharmacologic effects of cocaine associated with the inhibition of specific biogenic amine uptake systems is unknown. As part of a collaborative project affiliated with psychobiologists and psychopharmacologists at the National Institute of Drug Abuse, Addiction Research Center15 the specific aim of this research is directed toward the elucidation of the structural requirements for drug binding and drug efficacy at cocaine receptors of specific biogenic amine (serotonin, dopamine and norepinephrine) uptake sites. A multidisciplinary program consisting of chemical synthesis, pharmacologic evaluation and structural analysis will be employed to determine the structure-activity relationships (SAR) of cocaine and the cocaine receptor/biogenic amine uptake system. The specific areas of study with regard to the SAR of cocaine will include: (1) elucidation of the role of the carbomethoxy group, (2) determination of the importance of the rigid 8-aza-bicyclo[3.2.1]octane ring system and (3) evaluation of the importance of the relative proximity of the phenyl group to the cocaine nucleus (N(8) and carbomethoxy group). The initial approach for achieving the specific aims of this research will be to affect the stereoselective syntheses and the pharmacologic evaluation of compounds 3-13 (Chart I). The cocaine analogs will first be tested in in vitro paradigms for receptor affinity and for the ability of the compounds to inhibit dopamine, serotonin and norepinephrine uptake mechanisms. The pharmacologic activity of high affinity ligands will then be determined in vivo by assessment of the stimulant effects (locomotor stimulation, discriminative stimulus effects and reinforcing effects) of the drugs. This investigation should not only help to reveal the structural criteria for cocaine binding but should ultimately lead to the development of selective cocaine receptor mediated biogenic amine inhibitors. The availability of compounds of this nature should prove to be valuable tools for the resolution of the various pharmacologic effects of cocaine. Moreover, cocaine receptor mediated biogenic amine inhibitors can potentially be employed as cocaine antagonists and should prove useful for the treatment of cocaine addiction and overdose.17,18 The effects of the active compounds on cocaine overdose and toxicity will also be examined.
|Lomenzo, S A; Izenwasser, S; Katz, J L et al. (1997) Synthesis, structure, dopamine transporter affinity, and dopamine uptake inhibition of 6-alkyl-3-benzyl-2-[(methoxycarbonyl)methyl]tropane derivatives. J Med Chem 40:4406-14|
|Xu, L; Kelkar, S V; Lomenzo, S A et al. (1997) Synthesis, dopamine transporter affinity, dopamine uptake inhibition, and locomotor stimulant activity of 2-substituted 3 beta-phenyltropane derivatives. J Med Chem 40:858-63|
|Chen, Z; Izenwasser, S; Katz, J L et al. (1996) Synthesis and dopamine transporter affinity of 2-(methoxycarbonyl)-9-methyl-3-phenyl-9-azabicyclo[3.3.1]nonane derivatives. J Med Chem 39:4744-9|
|Aronson, B; Enmon, J L; Izenwasser, S et al. (1996) Synthesis and ligand binding of eta(6)-(2beta-carbomethoxy-3beta-phenyltropane) transition metal complexes. J Med Chem 39:1560-3|