期刊
TRENDS IN PHARMACOLOGICAL SCIENCES
卷 32, 期 3, 页码 148-157出版社
ELSEVIER SCIENCE LONDON
DOI: 10.1016/j.tips.2010.12.003
关键词
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Dopamine D-2-like receptors (including D-2, D-3 and D-4) belong to the 'rhodopsin-like' family of G protein-coupled receptors (GPCRs), which represent the largest group of targets for bioactive molecules. Due to their high sequence similarity, the design of subtype-selective ligands requires rational and effective strategies. The general formula of 1,4-disubstituted aromatic piperidines and piperazines (1,4-DAPs) was extracted from classical dopaminergic drugs. The biological properties of this compound family are encoded by an aromatic head group that controls intrinsic activity, an amine moiety and a lipophilic appendage. D-3- and D-4-selective molecular probes and drug candidates were generated from the general formula of 1,4-DAP. Formal structural rearrangement led to investigational drugs beyond the 1,4-DAP structure. The very recent publication of the Xray crystal structure of D-3 should facilitate efficient discovery of unprecedented chemotypes. However, the development of D-3-selective agonists, functionally selective ligands and the exploitation of homo- and heteromers remain challenging.
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