Dopaminergics

Y C, M G Bures, A A Danaher, J DeLazzer, I Lico and P A Pavlik 1993. A Fast New Approach to irmacophore Mapping and its Application to Dopaminergic and Benzodiazepine Agonists. mal of Computer-A ided Molecular Design 7 83-102. 

Unlike aniracetam, pramiracetam does not appear to interact with dopaminergic, serotonergic, or adrenergic neurotransmission (72). The agent inhibits prolylendopeptidase in certain brain areas, but its inhibition constant, iC, is only 11 ]lM (69). The absence or weak activity of this compound with various neuronal systems appears to make it less likely to be of significant therapeutic value than other members of this class of agents. 

Correlation between clinical effectiveness and receptor affinities, however, can be seen with other receptors in addition to the dopamine D2 receptor. These include other dopaminergic receptors, as well as noradrenergic and serotonergic receptors. For example, most antipsychotics also have high affinity for a -adrenoceptors and 5-HT2 receptors (225). Some antipsychotics have been shown to be selective for the adrenoceptor versus the a -adrenoceptor, for example, spiperone [749-02-0] (226) and risperidone (61) (221]... 

Catecholamines. Simphsticahy, the SNS is composed of nerves capable of synthesizing and releasing various catecholamines that can bind appropriate molecular receptors post-synapticahy. Dependent on their synthetic stmcture, they have the abhity to bind, and therefore stimulate various post-synaptic events through a, P, and dopaminergic receptors. 

Catecholamine biosynthesis begins with the uptake of the amino acid tyrosine into the sympathetic neuronal cytoplasm, and conversion to DOPA by tyrosine hydroxylase. This enzyme is highly localized to the adrenal medulla, sympathetic nerves, and central adrenergic and dopaminergic nerves. Tyrosine hydroxylase activity is subject to feedback inhibition by its products DOPA, NE, and DA, and is the rate-limiting step in catecholamine synthesis the enzyme can be blocked by the competitive inhibitor a-methyl-/)-tyrosine (31). 

The molecular modeling studies with this set of dopaminergic ligands involved the following analytical steps ... 

YC Martin, MG Bures, EA Danaher, I DeLazzer, I Lico, PA Pavlik. A fast new approach to pharmacophore mapping and its application to dopaminergic and benzodiazepine agonists. I Comput Aided Mol Des 7 83-102, 1993. 

Diastereomeric oxazolidines 88 and 89 (Scheme 8.4.27) were available via 1,4-reduction and cyclization of Zincke product 87, with 88 being the kinetic product under the reaction conditions and 89 (X-ray) the thermodynamically favored isomer in CDCI3 solution. Iterative reductive oxazolidine opening provided 3-aryl piperidine 91, which was readily advanced to (-)-PPP (92), a selective dopaminergic receptor antagonist. ... 

Deca/octahydro 6-alkyloxazolo /-fused quinolines 17 were prepared and evaluated as dopaminergics (87EUP1). A series of linearly annelated 8-alkyl-deca/ octahydrooxazoloquinolines 18 and their salts were prepared for use as dopamine D2-agonists and hypertensive agents. The rran.s-( )-l-propyl-6-oxodecahydro-quinoline was brominated, then treated with urea in methanol to give the 2-amino... 

Trepipam (69) is a sedative agent apparendy acting via dopaminergic mechanisms. It can be synthesized by attack on the less hindered terminus of styrene oxide (66) by 4,5-dimethoxyphe-nethylamine (65) to give 67. Cyclodehydration catalyzed by strong acid then leads to 68 and N-... 

Neuromelanin, a dark colored pigment and product of the oxidative metabolism of dopamine, is found in the cytoplasm of dopaminergic neurons of the human substantia nigra pars compacta. Neuromelanin deposits increase with age, matching the age distribution of Parkinson s disease. In the absence of significant quantities of iron, neuromelanin can act as an antioxidant in... 

Kaxp channels under investigation resulted in selective rescue of substantia nigra dopaminergic neurons does not prove a deleterious, neurodegeneration-promoting role of Katp channels, but may simply mean that the dopamine neurons, lacking KATP channels, have developed other, undetected self-protection mechanisms. 

While advances in the symptomatic drug therapy (summarized below) have certainly improved the lives of many Parkinson patients, the goal of current research is to develop treatments that can prevent, retard or reverse the death of dopaminergic neurons in the substantia nigra pats compacta (and of other neurons involved in the pathogenesis of Parkinson s disease not mentioned in this essay). 

Liss B, Haeckel O, Wildmann J et al (2005) K-ATP channels promote tire differential degeneration of dopaminergic midbrain neurons. Nat Neurosci 8 1742-1751... 

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