Table 4.

mGlu₃ NAM and mGlu₅ SAR of 5-Fluoropyridin-2-yl Ether Analogues 55–72

no.	R	mGlu3 pIC50 (± SEM)a	mGlu3 IC50 (nM)a	% Glu Max (± SEM)a,b	mGlu5 activityc	mGlu5 pEC50 (± SEM)c	mGlu5 EC50 (nM)c	% Glu Max (± SEM)b,c
55	2-fluorophenyl	6.79 ± 0.17	162	1.53 ± 0.12	NAMf	<5.0	>10000	29.1 ± 7.3
56	3-fluorophenyl	6.72 ± 0.08	192	1.44 ± 0.38	NAM	5.56 ± 0.24	2720	9.71 ± 5.78
57	2-chlorophenyl	6.85 ± 0.16	141	1.37 ± 0.72	NAM	6.00 ± 0.25	1010	8.78 ± 5.29
58	3-chlorophenyl	6.84 ± 0.10	145	2.30 ± 0.17	NAMe	5.73 ± 0.24	1850	19.2 ± 10.0
59	4-chlorophenyl	6.71 ± 0.13	197	2.17 ± 0.40	PAM	6.44 ± 0.03	364	51.6 ± 7.7
60	2-methylphenyl	6.46 ± 0.06	346	1.72 ± 0.16	NAMf	<5.0d	>10000d	35.8d
61	3-methylphenyl	6.67 ± 0.15	216	1.93 ± 0.56	NAMf	<5.0	>10000	36.6 ± 8.7
62	4-methylphenyl	6.57 ± 0.03	269	1.04 ± 0.45	NAMf	<5.0	>10000	54.8 ± 9.4
63	2-methoxyphenyl	6.47 ± 0.10	339	1.49 ± 0.60	NAM	6.52 ± 0.17	301	3.28 ± 0.45
64	3-methoxyphenyl	6.70 ± 0.06	198	1.02 ± 0.12	NAMf	<5.0	>10000	59.7 ± 6.1
65	4-methoxyphenyl	6.49 ± 0.10	320	1.23 ± 0.38	PAM	5.86 ± 0.05	1380	32.3 ± 5.2
66	2,3-difluorophenyl	6.73 ± 0.16	184	2.15 ± 0.33	NAMe	5.68 ± 0.20	2110	21.0 ± 10.6
67	2,5-difluorophenyl	6.91 ± 0.11	123	2.62 ± 0.47	NAMf	<5.0	>10000	18.8 ± 6.1
68	2,6-difluorophenyl	6.74 ± 0.08	181	1.49 ± 0.17	NAMe	5.91d	1230d	50.8d
69	pyridin-2-yl	6.04 ± 0.05	915	0.96 ± 0.63	NAM	5.45 ± 0.04	3520	3.71 ± 0.47
70	pyridin-3-yl	6.36 ± 0.13	436	0.64 ± 0.70	NAMf	<5.0	>10000	46.3 ± 2.9
71	pyridin-4-yl	6.05 ± 0.04	881	0.77 ± 0.44		<4.5	>30000
72	5-fluoropyridin-2-yl	6.46 ± 0.07	349	1.31 ± 0.11	NAM	5.01 ± 0.13	9740	7.0 ± 2.5

^aCalcium mobilization mGlu₃ assay; values are average of n ≥ 3.

^bAmplitude of response in the presence of 30 μM test compound as a percentage of maximal response (100 μM glutamate); average of n ≥ 3.

^cCalcium mobilization mGlu₅ assay; values are average of n ≥ 3.

^dAverage of n = 2.

^ePartial NAM; CRC plateaus above 10% glutamate maximum.

^fWeak activity; CRC does not plateau.