Stepwise modulation of neurokinin-3 and neurokinin-2 receptor affinity andselectivity in quinoline tachykinin receptor antagonists

A stepwise chemical modification from human neurokinin-3 receptor (hNK-3R)- selective antagonists to potent and combined hNK-3R and hNK-2R antagonists using the same 2-phenylquinoline template is described. Docking studies wit h 3-D models of the hNK-3 and hNK-2 receptors were used to drive the chemic al design and speed up the identification of potent and combined antagonsit s at both receptors. (S)-(+)-N-( l-Cyclohexylethyl)-3-[(4-morpholin-4-yl)pi peridin- l-yl]methyl-2-phenylquinoline-4-carboxamide (compound 25, SB-40023 8: hNK-3R binding affinity, K-i = 0.8 nM; hNK-2R binding affinity, Ki = 0.8 nM) emerged as the best example in this approach. Further studies led to t he identification of (S)-(+)-N- 1,2,2-trimethylpropyl)-3- [(4-piperidin- l- yl)piperidin- l-yl] methyl-2-phenylquinoline-4-carboxamide (compound 28, SB -414240: hNK-3R binding affinity, K-i = 193 nM; hNK-BR binding affinity, K- i = 1.0 nM) as the first hNK-2R-selective antagonist belonging to the 8-phe nylquinoline chemical class. Since some members of this chemical series sho wed a significant binding affinity for the human mu -opioid receptor (hMOR) , docking studies were also conducted on a 3-D model of the hMOR, resulting in the identification of a viable chemical strategy to avoid any significa nt mu -opioid component. Compounds 25 and 28 are therefore suitable pharmac ological tools in the tachykinin area to elucidate further the pathophysiol ogical role of NK-3 and NK-2 receptors and the therapeutic potential of sel ective NK-2 (28) or combined NK-3 and NK-2 (25) receptor antagonists.