Dopamine pharmacophores

This chapter describes the synthesis and in vitro pharmacology of a novel series of dopamine receptor ligands, in which the classical phenylethylamine pharmacophore is replaced by a thienylethylamine moiety. In general, the novel compounds showed moderate affinity for the dopamine D2 and D3 receptors. The results showed that a thienylethylamine moiety can act as a dopamine pharmacophore on these receptors. When the thienylethylamine moiety is fixed in a rigid system the affinity for the dopamine receptor is increased, however, in the tricyclic hexahydrothianaphthoxazine structure, the affinity for the dopamine receptors is diminished. 

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.

DM Mottola, S Laiter, VJ Watts, A Tropsha, SW Wyrick, DE Nichols, P Mailman. Conformational analysis of d dopamine receptor agonists Pharmacophore assessment and receptor mapping. J Med Chem 39 285-296, 1996. 

Varady J, Wu X, Fang X, Min J, Hu Z, Levant B, Wang S. Molecular modeling of the three-dimensional structure of dopamine 3 (D3) subtype receptor discovery of novel and potent D3 ligands through a hybrid pharmacophore-and structure-based database searching approach. / Med Chem 2003 46 4377-92. 

Figure 8. Angular relationships of pharmacophores in drugs acting at dopamine receptors (8).

Figure 13.3 Two rotamers of dopamine and derived pharmacophore models (adapted from [25]). A H-bond acceptor, D H-bond donor,...

P positively charged, L lipophilic. The pharmacophore model on the right resulted from inspection of several other dopamine receptor ligands, which led to a single remaining donor site at one of the hydroxyl groups. 

An example may help to clarify this statement Figure 13.4 shows the 10 highest-ranking compounds that were retrieved from the COBRA database by a topological pharmacophore similarity search (CATS method, see below). The query structure was Haloperidol, a dopamine (D2) receptor antagonist. Not surprisingly classic variations of the query structure are found in ranks 1 and 2. These are not very... 

Figure 13.14 Projection of two promiscuous binders, Sertindole (primary target 5-HT2a, left) and Clozapine (primary target D4.2, right), onto the COBRA SOM. The distribution of known serotonin receptor ligands is shown in the left map, the distribution of known dopamine receptor ligands is shown in the right map. The colored areas of the two maps overlap, indicating similar activity of the compounds. Blue few compounds red many compounds crosses indicate unpopulated areas of pharmacophore space.

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