Table 1.

Efficacy and potency of substituted pyrazoloquinolinones/ pyrazolopyridinones at α1β3 GABA_A receptors, as well as their affinity for the benzodiazepine binding site of α1β3γ2 GABA_A receptors. Top: Pyrazolo[4, 3-c]quinolin-3-one nucleus; Left: Different substituents and whole chemical structure of pyrazoloquinolinones/ pyrazolopyridinones investigated; Right, α1β3 receptor data: Efficacy (10 μM) and potency (EC₅₀ for positive modulators and IC₅₀ for null modulators) of pyrazoloquinolinones/pyrazolopyridinones in recombinant rat α1β3 receptors expressed in Xenopus laevis oocytes, obtained by TEV electrophysiology. EC₅₀/IC₅₀ values were computed by GraphPad Prism. Data represent means ± SEM (n = 4–12); α1β3γ2 receptor data: previously published affinities (K_i/IC₅₀) of the compounds for the benzodiazepine binding site of GABA_A receptors (for references and methods used, see table footnote)

						α1β3			α1β3γ2
	Compounds	R8	R7	R6	R4′	R3′	10 μM	EC50 / IC50* (μM)	Ki / IC50 (nM)
1	CGS 8216	H	H	H	H	H	156 ± 18	22 ± 10.2	0.17 ± 0.01a
2	CGS 9896	H	H	H	Cl	H	245 ± 5	11 ± 6.8	0.5 ± 0.1b
3	CGS 9895	H	H	H	OMe	H	413 ± 25	9.5 ± 3.8	0.32 ± 0.5a
4	XHe-III-063	H	H	H	C ≡ CH	H	474 ± 29	4.3 ± 1.2	0.073c
5	PWZ-009A1	H	OMe	H	H	H	154 ± 3	15 ± 4.6	1.3c
6	PZ-II-029	H	OMe	H	OMe	H	213 ± 3	26 ± 10.7	0.3c
7	XHe-III-006c	H	Br	H	Br	H	110 ± 1	>10	34c
8	XHe-II-087c	H	H	tBu	Br	H	196 ± 14	6.1 ± 1.5	7000c
9	LAU 163	Cl	H	H	H	H	151 ± 2	1.2 ± 0.2	N/D
10	LAU 156	Cl	H	H	CH3	H	372 ± 40	2.3 ± 1.0	N/D
11	PZ-II-028	Cl	H	H	OMe	H	1079 ± 81	1.6 ± 0.4	0.2c
12	LAU 161	Cl	H	H	CN	H	300 ± 23	0.4 ± 0.1	N/D
13	LAU 206	Cl	H	H	NH2	H	360 ± 36	0.6 ± 0.4	N/D
14	LAU 162	Cl	H	H	COOEt	H	140 ± 7	0.8 ± 0.4	N/D
15	LAU 157	Cl	H	H	NO2	H	n.s.	7.5 ± 1.1*	N/D
16	LAU 159	Cl	H	H	H	OMe	117 ± 10	2.2 ± 1.9	N/D
17	PWZ-007A	OMe	H	H	H	H	244 ± 6	4.5 ± 0.3	0.1c
18	LAU 176	OMe	H	H	OMe	H	1058 ± 61	3.8 ± 0.2	0.14 ± 0.09d
19	LAU 177	OMe	H	H	CN	H	1063 ± 128	1 ± 0.1	0.75 ± 0.81d
20	XHe-III-24	tBu	H	H	F	H	266 ± 28	11 ± 1.7	0.25c
21	XHe-II-006	tBu	H	H	Br	H	216 ± 20	4.6 ± 1.9	4.7c
22	XHe-II-17	tBu	H	H	C≡CH	H	180 ± 12	3.8 ± 1.2	3.3c
23	XHe-II-094	tBu	H	H	C≡CSiMe3	H	n.s.	33 ± 7.5*	329c
24	XHe/ON-I	tBu	H	H	C≡CCH2SiMe3	H	112 ± 2	>10	N/D
25	XHe-II-019	tBu	H	H	C≡C–C≡CtBu	H	n.s.	25 ± 6.9*	273c
26	PB-XHe	CH3	CH3	H	Br	H	112 ± 1	>10	108c
27	XHe-II-098b				Br	H	n.s.	38 ± 7.9*	7000c
28	XHe-II-098a				H	H	non-binder		4000c
29	XHe-II-098c				Cl	H	non-binder		6000c
30	CGS 20625						391 ± 19	8.5 ± 2.1	0.5 ± 0.1b
31	LAU 168						non-binder		N/D
32	XHe-III-67						484 ± 50	2.7 ± 0.6	>3000c
33	XHe-III-56						n.s.	35 ± 12.9*	1010c

^*IC₅₀ values obtained by the inhibition of [300 nM] compound 11 effect on GABA EC3 current; n.s., not significant; N/D, not determined.

^aKi: Displacement of [³H]Ro15-1788 binding to human α1β3γ2 receptors (mean ± SEM, n = 3–6) (Smith et al., 2001).

^bKi: Displacement of [³H]flunitrazepam binding to mouse brain membranes without cerebellum (mean ± SD, n = 6–9) (Ogris et al., 2004).

^cKi: Displacement of [³H]Ro15-1788 binding to Ltk-cells expressing human α1β3γ2 receptors. Data are the means of two determinations, which differed by less than 10%. (He et al., 1999; Yu et al., 1999; He, 2000).

^dIC₅₀: Displacement of [³H]Ro15-1788 binding in a mouse cerebellar membrane (three times in triplicates; means ± SEM).

Italic EC₅₀ values represent estimated values due to unsaturated compound dose response curves.