Stepwise Modulation of Neurokinin-3 and Neurokinin-2 Receptor Affinity and Selectivity in Quinoline Tachykinin Receptor Antagonists

Abstract

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 with 3-D models of the hNK-3 and hNK-2 receptors were used to drive the chemical design and speed up the identification of potent and combined antagonsits at both receptors. (S)-(+)-N-(1-Cyclohexylethyl)-3-[(4-morpholin-4-yl)piperidin-1-yl]methyl-2-phenylquinoline-4-carboxamide (compound 25, SB-400238: hNK-3R binding affinity, K(i) = 0.8 nM; hNK-2R binding affinity, K(i) = 0.8 nM) emerged as the best example in this approach. Further studies led to the identification of (S)-(+)-N-(1,2,2-trimethylpropyl)-3-[(4-piperidin-1-yl)piperidin-1-yl]methyl-2-phenylquinoline-4-carboxamide (compound 28, SB-414240: hNK-3R binding affinity, K(i) = 193 nM; hNK-2R binding affinity, K(i) = 1.0 nM) as the first hNK-2R-selective antagonist belonging to the 2-phenylquinoline chemical class. Since some members of this chemical series showed 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 significant micro-opioid component. Compounds 25 and 28 are therefore suitable pharmacological tools in the tachykinin area to elucidate further the pathophysiological role of NK-3 and NK-2 receptors and the therapeutic potential of selective NK-2 (28) or combined NK-3 and NK-2 (25) receptor antagonists.

Differences in the Central Nervous System Distribution and Pharmacology of the Mouse 5-Hydroxytryptamine-6 Receptor Compared with Rat and Human Receptors Investigated by Radioligand Binding, Site-Directed Mutagenesis, and Molecular Modeling

“…The extracellular loop regions were subsequently added using a procedure developed in house, which makes use of a combined distance-geometry sampling and molecular-dynamics simulation (Blaney et al, 2001). The final rat and human receptor models were generated in a similar manner.…”

Mutagenic Mapping Suggests a Novel Binding Mode for Selective Agonists of M1 Muscarinic Acetylcholine Receptors

“…These alignments were used with the standard homology modeling tools in the Quanta program to construct the seven helical bundle domain of M 1 . The extracellular loop regions were subsequently added using a procedure developed within GlaxoSmithKline (Harlow, Essex, UK), which makes use of a combined distance geometry sampling and molecular dynamics simulation (Blaney et al, 2001) The side chains of this model were then refined using the Karplus standard rotamer library (Dunbrack and Karplus, 1993). The final model was optimized fully (500 steps of Steepest Descent followed by 5000 steps of Adopted Basis Newton Raphson) with the CHARMM force field (Brooks et al, 1983) using helical distance constraints between the ith and i ϩ 4th residues (except proline) within a range of 1.8 to 2.5Å to maintain the backbone hydrogen bonds of the helix bundle.…”

Roof and Floor of the Muscarinic Binding Pocket: Variations in the Binding Modes of Orthosteric Ligands

“…These alignments were used with the standard homology modeling tools in the Quanta program to construct the seven helical bundle domain of the M 1 receptor. The extracellular loop regions were subsequently added using a procedure developed in-house that makes use of a combined distance geometry sampling and molecular dynamics simulation (Blaney et al, 2001). The side chains of this model were then refined using the Karplus standard rotamer library (Dunbrack and Karplus, 1993).…”