Based Subtype Pharmacophores

One of the early examples of pharmacophore modeling of the ala- and aib-AR subtypes was carried out by means of the Apex-3D software [100]. The common features of the pharmacophore models of the two arAR subtypes were a protonated amine, an aromatic ring and a polar region. The main difference between the two pharmacophores was the distance between the aromatic ring and the amine function. 

Finally, the five-feature a pharmacophore was generated from those ald antagonists, which were 100-fold selective over ala and 40-fold selective over alb receptors. The pharmacophore consisted of the following features (a) one positive ion, (b) one aromatic ring, (c) one H-bonding acceptor and (d) two hydrophobic groups [102]. 

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Supermolecule-Based Subtype Pharmacophore and QSAR Models... 

Receptor-Based Subtype Pharmacophore and Ligand-Target/Antitarget Interaction-Based QSAR... 

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. 

A series of 2-amino-3/4-dihydro quinazolines have been extensively explored as selective T-type calcium channel antagonists. A recent disclosure included KYS05090 (9) with an IC50 of 41 nM on the Cav3.1 subtype of the T-type channel and 120-fold selectivity versus the N-type calcium channel Cav2.2 [55]. A pharmacophore model was recently published based on this and related structures [56], but no other selectivity or in vivo activity have been disclosed since the original report. 

The above examples of peptide scaffold- or nonpeptide template-based peptidomimetic agonists or antagonists illustrate various strategies to elaborate bioactive conformation and/or pharmacophore models of peptide ligands at their receptors. In many cases, receptor subtype selectivity has also been achieved by systematic structural modifications of prototypic leads of peptidomimetics. Thus, although the 3D structures of G-protein-coupled receptors (GPCRs) remain as elusive (except for models constructed from homology-based low-... 

Bureau, R., Daveu, C., Lancelot, J.C. and Rault, S. (2002a) Molecular design based on 3D-pharmacophore. Application to 5-HT subtypes receptors./. Chem. Inf. Comput. Sci., 42, 429—436. 

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