Dopamine receptor structure

Application of the CCM to small sets (n < 6) of enzyme inhibitors revealed correlations between the inhibitory activity and the chirality measure of the inhibitors, calculated by Eq. (26) for the entire structure or for the substructure that interacts with the enzyme (pharmacophore) [41], This was done for arylammonium inhibitors of trypsin, Di-dopamine receptor inhibitors, and organophosphate inhibitors of trypsin, acetylcholine esterase, and butyrylcholine esterase. Because the CCM values are equal for opposite enantiomers, the method had to be applied separately to the two families of enantiomers (R- and S-enantiomers). 

Figure 3 The chemical structures of the ligands used in the molecular modeling study of the Di dopamine receptor. The ligands were divided into two groups (active and inactive) based on their pharmacological properties. The hypothesized pharmacophoric elements are shown in bold.

Strange, PG (1996) Dopamine receptors studies on structure and function. Adv. Drug Res. 28 ... 

Chlorpromazine is technically described as a phenothiazine, as are thioridazine and fluphenazine. Together with their structural analogues the thioxanthenes (e.g., clopenthixol) and the butyrophenones (e.g., haloperidol), the phenothiazines comprise the three major families of typical neuroleptics. They were developed in the late 1950s and early 1960s (Table 11.3). All these drugs block dopamine receptors, principally the D2 subtypes, with an affinity that correlates highly (r = +0.90) with their clinical... 

FIGURE 46-5 Chemical structures of dopamine receptor agonists. 

Watts VJ, Lawler CP, Fox DR, Neve KA, Nichols DE, Mailman RB. (1995). LSD and structural analogs pharmacological evaluation at D1 dopamine receptors. Psychopharmacology (Berlin). 118(4) 401-9. Wei D, Maisonneuve IM, Kuehne ME, Glick SD. (1998). Acute iboga alkaloid effects on extracellular serotonin (5-HT) levels in nucleus accumbens and striatum in rats. Brain Res. 800(2) 260-68. 

Consistent with this proposal, some post-mortem analyses of the brains of patients have shown either an increased concentration of dopamine or an increase in the number of dopamine receptors in the forebrain. These analyses have provided no indication of degeneration of neurones in the brain, but gross structural abnormalities are present the ventricles are enlarged and the cortex is thinner compared with normal brains. This suggests a disorder of development of the brain but how this could give rise to overactivity of the dopamine system in the forebrain is not known. 

Missale C et al. Dopamine receptors From structure to function. Physiol Rev 1998 78 189-225. 

Many compounds have been evaluated for their effects on brain metabolism (London, 1993). A surprisingly limited number of common regional metabolic effects have been seen within drug classes. Antipsychot ics, especially the older typical antipsychotics, tend to be associated with changes in striatal metabolism consistent with the high density of D2 dopamine receptors in those brain structures (Cohen et al.. 1999). On the other hand, quite different patterns of metabolic effects have been seen following acute doses with paroxetine and fluoxetine, both of which are selective serotonin... 

One common denominator of all antipsychotics is the biockade of centrai dopamine (DA) receptors. As a result, extrapyramidal reactions, particularly parkinsonian symptoms, are a major adverse effect of many of these drugs, as well as an important clue to their mechanism of action. True Parkinson s disease is caused by a DA deficiency in the nigrostriatal system. Further, crystallographic data have demonstrated that CPZ s molecular configuration is similar to that of DA, which could explain its ability to block this neurotransmitter s receptors. Drugs with similar structures that do not block DA receptors (e.g., promethazine, imipramine) do not have antipsychotic activity. Another example is the isomer of flupenthixol, which blocks DA receptors is an effective antipsychotic, but the isomer that does not is ineffective (7). The other family of dopamine receptors, D and Dg, have not yet been implicated in psychosis. 

Amoxapine has been found to be effective in several double-blind studies (Table 7-4 and Table 7-6). It is a dibenzoxazepine derivative that has both NE and serotonin uptake inhibiting properties. Amoxapine is converted into 8-hydroxyamoxapine, which has considerable dopamine receptor binding properties (i.e., radioreceptor bioassays on patients given amoxapine have found activity levels similar to those of patients on typical antipsychotics), a chemical structure similar to loxapine, and effects similar to antipsychotics (1Q3). As a result of this metabolite, amoxapine theoretically may have unique beneficial effects in psychotically depressed patients. However, this possibility has never been adequately tested. Nevertheless, this metabolite is likely responsible for some of the antidopamine effects reported in patients taking amoxapine, including acute and chronic extrapyramidal side effects and elevated prolactin levels ( 104). Like TCAs, amoxapine can be lethal in... 

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