Structure-activity relationships in a novel series of 7-substituted-aryl quinolines and 5-substituted-aryl benzothiazoles at the metabotropic glutamate receptor subtype 5

Abstract

The metabotropic glutamate receptor subtype 5 (mGluR5) has been implicated in numerous neuropsychiatric disorders including addiction. We have discovered that the rigid diaryl alkyne template, derived from the potent and selective noncompetitive mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP), can serve to guide the design of novel quinoline analogues and pharmacophore optimization has resulted in potent mGluR5 noncompetitive antagonists (EC(50) range 60-100 nM) in the quinoline series.

Figure 1

mGluR5 antagonist structural templates.

Figure 2

Compound 31 as a partial antagonist

Figure 3. 3D-superimposition of 8a (alkyne) and 32 (quinoline).

Note: Compound 32 is shown in turquoise blue and 8a in orange on right side for clarity.

Figure 4. 3D-superimposition of 8d (alkyne) and 26 (benzothiazole).

Note: Compound 8d is shown in turquoise blue and 26 in orange on right side for clarity.

Figure 5

3D-superimposition of quinoline analogues.

Scheme 1^a

^a Reagents and conditions: (a) Na₂CO₃, Pd(OAc)₂, dioxane, H₂O, 50 °C, overnight; (b) Trifluoromethanesulfonic anhydride, pyridine, CH₂Cl₂, RT, 2–5 h; (c) K₃PO₄, Pd(PPh₃)₄, Dioxane, 85 °C, overnight.

Scheme 2^a

^a Reagents and conditions: (a) Na₂CO₃, Pd(PPh₃)₄, DME, H₂O, 80 °C, overnight; (b) CF₃COOH, CH₂Cl₂, RT, 3 h; (c) H₂, 40 psi, Pd/C, ethanol, overnight.

Scheme 3^a

^a Reagents and conditions: (a) DBH, H₂SO₄, TFA; (b) Na₂CO₃, Pd(PPh₃)₄, DME, H₂O, 70 °C, overnight; (c) K₃PO₄, Pd(OAc)₂, ligand 1L, dioxane, H₂O, 105 °C, 16–20 h

Scheme 4^a

^a Reagents and conditions: (a) Pd(PPh₃)₂Cl₂, CuI, NEt₃, RT, overnight; (b) Pd(PPh₃)₄, CuI, Et₃N, DMF, TBAF, 70 °C.

Scheme 5^a

^a Reagents and conditions: (a) POCl₃, PCl₅, reflux overnight; (b) Na₂CO₃, PdCl₂(dppf), dioxane, H₂O, MW, 140 °C, 30 min; (c) K₃PO₄, Pd(OAc)₂, ligand 1L, dioxane, H₂O, MW 140 °C, 90 min.