Template selection and refinement considerations for modelling aminergic GPCR-ligand complexes.

G protein-coupled receptors (GPCRs) are important targets for development of drugs for the treatment of many diseases. However, crystal structures are available for only a small fraction of these membrane bound proteins. Accurate homology models will provide opportunities for effective drug design targeting GPCRs. Recently, several serotonin receptor crystal structures were solved and needed to be evaluated as potential templates. In the first part of this work different measures of similarity in template selection were explored and methods for homology modelling, docking and refinement of aminergic GPCR-ligand complexes were developed and evaluated by comparing models of the D3-R/eticlopride complex with the crystal structure. Homology models of the three α1 adrenergic receptor subtypes and of a serotonin receptor subtype were then constructed using these methods These models were evaluated by docking a range of antagonists into them.

Human α1-adrenoceptor subtype selectivity of substituted homobivalent 4-aminoquinolines.

A series of ring-substituted ethyl- and heptyl-linked 4-aminoquinoline dimers were synthesized and evaluated for their affinities at the 3 human α(1)-adrenoceptor (α(1)-AR) subtypes and the human serotonin 5-HT(1A)-receptor (5-HT(1A)-R). We find that the structure-specificity profiles are different for the two series at the α(1)-AR subtypes, which suggests that homobivalent 4-aminoquinolines can be developed with α(1)-AR subtype selectivity. The 8-methyl (8-Me) ethyl-linked analogue has the highest affinity for the α(1A)-AR, 7 nM, and the greatest capacity for discriminating between α(1A)-AR and α(1B)-AR (6-fold), α(1D)-AR (68-fold), and the 5-HT(1A)-R (168-fold). α(1B)-AR selectivity was observed with the 6-methyl (6-Me) derivative of the ethyl- and heptyl-linked 4-aminoquinoline dimers and the 7-methoxy (7-OMe) derivative of the heptyl-linked analogue. These substitutions result in 4- to 80-fold selectivity for α(1B)-AR over α(1A)-AR, α(1D)-AR, and 5-HT(1A)-R. In contrast, 4-aminoquinoline dimers with selectivity for α(1D)-AR are more elusive, since none studied to date has greater affinity for the α(1D)-AR over the other two α(1)-ARs. The selectivity of the 8-Me ethyl-linked 4-aminoquinoline dimer for the α(1A)-AR, and 6-Me ethyl-linked, and the 6-Me and 7-OMe heptyl-linked 4-aminoquinoline dimers for the α(1B)-AR, makes them promising leads for drug development of α(1A)-AR or α(1B)-AR subtype selective ligands with reduced 5-HT(1A)-R affinity.