Figure 1.

‘Blue-print’ for the design of dualsteric receptor activators with subtype-selectivity. (A) Side view on the upper part of the muscarinic M₂ acetylcholine receptor. The free volume of the ligand binding pocket is lined by the grid structure. The model is based on the crystal structure of bovine rhodopsin in the inactive state. An inverse agonist (N-methylscopolamine) is docked into the orthosteric site to stabilize an inactive receptor conformation in the molecular dynamics simulation (modified from Voigtländer et al., 2003). The circle marks the allosteric core region which harbours non-conserved subtype-selectivity providing amino acids. (B) Design concept for subtype-selective allosteric/orthosteric hybrid agonists. The allosteric building block is derived from the alkane-bis-ammonio (ABA)-type compound W84, iperoxo (agonist d) is the orthosteric building block, the resulting hybrid compound is 1d.