Cocaine analogues

Rasmussen, S. G Carroll, F. I., Maresch, M. J., Jensen, A. D Tate, C. G and Gether, U. (2001) Biophysical characterization of the cocaine binding pocket in the serotonin transporter using a fluorescent cocaine analogue as a molecular reporter. J. Biol. Chem. 276, 4717 1723. 

The reinforcing effects of cocaine and cocaine analogues correlate best with their effectiveness in blocking the dopamine transporter, which leads to increased dopaminergic stimulation at critical brain sites. However, cocaine also blocks both norepinephrine (NE) and serotonin (5-HT) reuptake, and chronic use of cocaine produces changes in these neurotransmitter systems as measured by reductions in the neurotransmitter metabolites MHPG (3-methoxy-4 hydroxyphenethyleneglycol) and 5-HIAA (5-hydroxyindoleacetic acid). 

Robbins TW, Watson DA, Gaskin M, Ennis C (1983) Contrasting interactions of pipradrol, d-amphetamine, cocaine, cocaine analogues, apomorphine and other drugs with conditioned reinforc-mento. Psychopharmacol 50 113-119. 

Staley JK, Basile M, Flynn DD, Mash DC (1994a) Visualizing dopamine and serotonin transporters in the human brain with the potent cocaine analogue [125I]RTI-55 In vitro binding and autoradiographic characterization. J Neurochem 62 549-556. 

In subsequent investigations by the author, synthetic methods of the current invention were used to prepare tropane (4) and cocaine analogues (5). 

List all the bond terms you would need to describe the cocaine analogue ecgonine, 2.3. 

Because cocaine binds at the dopamine transporter, this provides a convenient method for the investigation and formulation of SARs these have been recently reviewed elsewhere (48,49). Important features for the binding of cocaine analogues include configuration, substituent at C2, stereochemistry at C2, substituent at Ns, and substituents at C3. With respect to cocaine analogues, inversion of configuration can decrease activity. The C2-position is quite important Epimerization from p to a reduces activity by 30- to 200-fold, and hydrolysis of the... 

Carroll FI, Lewin AH, Boja JW, et al. Cocaine receptor biochemical characterization and structure-activity relationships of cocaine analogues at the dopamine transporter. J Med Chem 35 969-981. 

A modified Hofmann cyclization of an oxyallyl cation to cocaine analogues was attempted. N-Methylpyrrole (16) and 2,4-dibromopentanone gave a fair yield of the cyclo-adduct (17) in the presence of copper and sodium iodide. However, the method did not prove useful for achieving the original aim, i.e. a cocaine analogue. 

Cocaine is a tropane-type derivative with several chiral centres and only the (lJ ,2f ,3S,5S)-stereoisomer, also called (—)-cocaine, appears to have appreciable psychostimulant properties. Its primary mode of action is based on blockage of the dopamine transporter which is defined as a directly mediated mechanism. Cocaine is therefore classified as a dopamine blocker rather than dopamine releaser, as is the case with some amfetamines. A large number of 2P,3P-cocaine analogues are well tolerated by the dopamine transporter but not necessarily by the noradrenaline or serotonin counterparts. This means that dopamine reuptake blockage alone is not necessarily sufficient to reinforce consumption, and appropriate stmctural modifications could lead to the development of treatment options for cocaine abuse. 

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