Dopamine transport blockers

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. 

The widespread presence of nicotinic receptors in the central nervous system coupled with the relative rarity of a classical synaptic role means that it is still difficult to describe a clear physiological role for these receptors. This is particularly true for receptors in presynaptic locations, for which the level and temporal pattern of exposure to the neurotransmitter are unknown. Approaches that are casting light on this problem include mouse knockout models and transmitter depletion by blockers of vesicular transport processes such as vesamicol the combination of these techniques has recently shown that normal evoked dopamine release in striatal slices is strongly dependent on endogenous cholinergic mechanisms that involve the activation of j32-containing nicotinic receptors (240). 

Uptake blocker (Table 12) display a certain degree of structural relatedness to the endogenous neurotransmitter whose transport is inhibited dopamine uptake by the anonaine, cocaine, ibogaine, and salsolinol (see Scheme II) serotonin by 12-hydroxyibogaine, ibogaine, and norharman noradrenaline and adrenaline by cathinone, ephedrine, salsolinol GABA by arecaidine, and guvacine. Reserpine and deserpidine... 

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