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. 2013 Nov 14;56(21):8352-65.
doi: 10.1021/jm400704g. Epub 2013 Oct 30.

Design, synthesis, and activity of a series of arylpyrid-3-ylmethanones as type I positive allosteric modulators of α7 nicotinic acetylcholine receptors

Derk J Hogenkamp  1 , Thomas A Ford-Hutchinson, Wen-Yen Li, Edward R Whittemore, Ryan F Yoshimura, Minhtam B Tran, Timothy B C Johnstone, Gavin D Bascom, Hannah Rollins, Lena Lu, Kelvin W Gee
Affiliations

Design, synthesis, and activity of a series of arylpyrid-3-ylmethanones as type I positive allosteric modulators of α7 nicotinic acetylcholine receptors

Derk J Hogenkamp et al. J Med Chem. .

Abstract

A series of novel arylpyrid-3-ylmethanones (7a-aa) were designed as modulators of α7 nicotinic acetylcholine receptors (nAChRs). The methanones were found to be type I positive allosteric modulators (PAMs) of human α7 nAChRs expressed in Xenopus ooctyes. Structure-activity relationship (SAR) studies resulted in the identification of compound 7v as a potent and efficacious type I PAM with maximum modulation of a nicotine EC5 response of 1200% and EC50 = 0.18 μM. Compound 7z was active in reversing the effect of scopolamine in the novel object recognition (NOR) paradigm with a minimum effective ip dose of 1.0 mg/kg (2.7 μmol/kg). This effect was blocked by the selective α7 nAChR antagonist methyllycaconitine (MLA). These compounds are potent type I positive allosteric modulators of α7 nAChRs that may have therapeutic value in restoring impaired sensory gating and cognitive deficits in schizophrenia and Alzheimer's disease.

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Figures

Figure 1
Figure 1
Structures of Type I and Type II PAMs
Figure 2
Figure 2
Structures of enaminone esters (1a and 1b), amide 1c and the E- and Z-isomers of 1a.
Figure 3
Figure 3
Design of (2-alkylamino-5-arylpyridine-3-yl)arylmethanones 2 from enaminone amide 1c.
Figure 4
Figure 4
Acetylcholine (ACh) concentration-response curves in the presence and absence of an EC50 concentration of compound 7z.
Figure 5
Figure 5
Modulation of nicotine EC5 evoked currents in Xenopus oocytes expressing human α7 nAChRs with increasing concentrations of 7z.
Figure 6
Figure 6
Current trace of 1µM 7z in the presence of 100 µM nicotine showing no reversal of desensitization
Figure 7
Figure 7
Effect of 7z (0.3 to 10 mg/kg, 0.81 to 27 µmol/kg) i.p. in 80% PEG 400/20% saline on the % time spent with a novel object (% novel time) in the mouse (CD-1) NOR paradigm in the presence of 0.7 mg/kg (2.1 µmol/kg) s.c. scopolamine hydrochloride (Scop) versus those treated with drug, vehicle and Scop alone. All animal groups received Scop. Significant One-way ANOVA P<0.0001. Post Hoc Dunnet’s Multiple Comparison Test **P<0.01. The effect of 3 mg/kg (8.1 µmol/kg) 7z is reversed by 3 mg/kg (3.4 µmol/kg) MLA (far right bar). Post Hoc Bonferroni’s Multiple Comparison Test ***P<0.001.
Figure 8
Figure 8
Dihedral angle (ψ) varied in conformational analysis
Scheme 1
Scheme 1
Method A: Synthesis of Arylpyridylmethanones Starting with Arylacetic Acids. Reagents/Solvents: a) POCl3/DMF/70 °C, then aq. NaOH/100 °C b) cyanoacetamide/NaOMe/MeOH c) POCl3, reflux d) R1NH2/DMSO e) R2PhMgX/THF reflux then aq. HCl, reflux f) MeNHPr/DMSO.
Scheme 2
Scheme 2
Method B: Conversion of 2-chloronicotinonitrile to 7l, m, n and o. Reagents/Solvents: a) Propylamine/DMSO b) NBS/DMF c) ArylB(OH)2, toluene/EtOH/aq. Na2CO3/Pd(PPh3)4 d) 4-Fluorophenylmagnesium bromide/THF, reflux then aq. HCl, reflux
Scheme 3
Scheme 3
Method C: Use of 2-fluoropyridine as starting material Reagents/Solvents: a) LDA/THF/R2PhCHO, −78 °C b) PCC/CH2Cl2 c) R1NH2/DMSO or EtOH, rt d) NBS/DMF e)4-EtOPhB(OH)2, toluene/EtOH/aq. Na2CO3/Pd(PPh3)4.
Scheme 4
Scheme 4
Reaction of 3-(3,4-difluorobenzoyl)-2-fluoropyridine (14) with amines.
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