2,3,7-Trisubstituted pyrazolo[1,5-d][1,2,4]triazines: Functionally selective GABAA α3-subtype agonists

Article abstract of DOI:10.1016/j.bmcl.2006.03.081

Novel synthetic routes have been devised for the preparation of previously inaccessible 2,3,7-trisubstituted pyrazolo[1,5-d][1,2,4]triazines 2. These compounds are high affinity ligands for the GABA_A benzodiazepine binding site and some analogu

Full text of DOI:10.1016/j.bmcl.2006.03.081

Bioorganic & Medicinal Chemistry Letters 16 (2006) 3550–3554
2,3,7-Trisubstituted pyrazolo[1,5-d][1,2,4]triazines: Functionally
selective GABAA a3-subtype agonists
Robert W. Carling,* Michael G. N. Russell, Kevin W. Moore, Andrew Mitchinson,
Alexander Guiblin, Alison Smith, Keith A. Wafford, George Marshall,
John R. Atack and Leslie J. Street
Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex, CM20 2QR, UK
Received 21 February 2006; revised 23 March 2006; accepted 24 March 2006
Available online 18 April 2006
Abstract—Novel synthetic routes have been devised for the preparation of previously inaccessible 2,3,7-trisubstituted pyrazolo-
[1,5-d][1,2,4]triazines 2. These compounds are high affinity ligands for the GABAA benzodiazepine binding site and some analogues
show functional selectivity for agonism at a3-containing receptors over a1-containing receptors with the lead compound being 32.
ꢀ 2006 Elsevier Ltd. All rights reserved.
GABA (c-aminobutyric acid) is the major inhibitory
neurotransmitter in the brain1 and GABAA receptors
constitute the largest population of inhibitory neuro-
transmitter receptors.2 The purification, sequencing
and cloning of the GABAA receptor have led to the
identification of sixteen subunits (a1–a6, b1–b3, c1–c3,
d, e, p and h).3 Expression of recombinant receptors
shows that at least one a, one b and one c (or d or e)
subunit is required to form a pentameric, functional
GABA-gated chloride ion channel,3,4 with recent studies
suggesting a subunit stoichiometry of two a, two b and
one c subunit.5 As well as an agonist (GABA) binding
site, GABAA receptors also have multiple allosteric
modulatory sites for barbiturates, neurosteroids, anaes-
thetics, avermectins and benzodiazepines which all mod-
ulate opening of the channel.6 Of these, the
benzodiazepine (BZ) site is the best characterised due
to its role in mediating the clinical effects of anxiolytics
such as diazepam.
It has been shown that the major benzodiazepine sen-
sitive GABAA receptor subtypes in brain are a1bc2,
a2bc2, a3bc2 and a5bc2.4 Currently used anxiolytic
benzodiazepines such as diazepam are nonselective,
high efficacy agonists and these compounds show sed-
ative,7 muscle-relaxant8 and amnesic9 properties.
Zolpidem, which has higher affinity for a1- (the major
subtype of GABAA receptors in the CNS)4 over a2-,
a3- and a5- containing receptors is particularly seda-
tive in animal tests and in human.10 This suggests that
compounds with reduced affinity and/or efficacy at a1-
containing GABAA receptors, yet with affinity and
efficacy at a2- and/or a3-subtypes, may retain the
desirable anxiolytic activity of nonselective benzodiaze-
pines and possess an improved side-effect profile (i.e.,
reduced sedation). Further evidence for the role of
a1-containing receptors in sedation has been provided
by the use of transgenic mice in which the a1 subunit
was rendered BZ insensitive.11,12 In these animals, the
anxiolytic, anticonvulsant and myorelaxant effects of
diazepam were preserved, while its sedative and amne-
sic effects were significantly reduced. To date, only a
limited number of GABAA a2/3 subtype selective
ligands have been reported in the literature.12–16 We
disclosed a series of triazolophthalazines as GABAA
a2/3 agonists which had moderately higher affinity
at a2- and a3- compared to a1-containing receptors17
and we recently reported on series of triazolopyrida-
zines,18 imidazopyrimidines,19 imidazotriazines20 and
imidazopyrazinones21 as functionally selective a2/a3
agonists. In this communication, we describe our
H3C
N
O
N
CH3
N(CH3)2
N
N
H3C
Cl
O
Diazepam
Zolpidem
Keywords: GABAA-Benzodiazepine-modulatory-site; Subtype-selec-
tive-agonists; Pyrazolo[1,5-d][1,2,4]triazines.
*
Corresponding author. Tel.: +44
robert.carling@virgin.net
0
1279 503044; e-mail:
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.03.081

R. W. Carling et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3550–3554
3551
efforts in designing, synthesising and optimising a nov-
el series of pyrazolotriazines as functionally selective
GABAA a3 agonists.
OH
NH
OH
HO
i
ii
O
NH
N
N
Cl
O
68%
O
N
OH
5
N
38%
Compounds were tested for their ability to inhibit the
binding of [3H]Ro15-1788 to the benzodiazepine binding
site of different a subunit-containing (b3,c2, plus either an
a1 or a3) human recombinant GABAA receptors stably
expressed in L(tkÀ) cells.22 As a general screen for effica-
cy, modulation of chloride ion flux in cellsexpressing b3c2
plus either a1 or a3 produced by an EC20 equivalent con-
centration of GABA in the presence of an approximate
1000 · Ki concentration of test compound was carried
out. Efficacy is expressed relative to the full agonist chlo-
rodiazepoxide (relative efficacy = 1.0), from at least seven
independent experiments.23 For key compounds, effica-
cies were re-checked using whole-cell patch-clamp record-
ings from L(tkÀ) cells stably expressing a1b3c2 or a3b3c2
GABAA receptor subtypes using increasing concentra-
tion of test ligand to measure the concentration re-
sponse.14,24 In all cases, good agreement was observed.23
4
N
3
N
N
N
90%
O
iii
F
O
F
N
N
N N
H
H
N
NH
NH
N
iv
N
v
N
81%
34%
O
O
O
N
N
N
N
N
N
N
N
8
6
7
N
Scheme 1. Reagents and conditions: (i) NH2NH2ÆH2O, EtOH, reflux, 10
days; (ii) K2CO3, DMF; (iii) MnO2, CHCl3, reflux, 8 h; (iv) 2-
fluorobenzhydrazide, xylene, reflux, 1 h; (v) Dowtherm A, 200 ꢁC, 30 h.
Ar
Ar
Ar
N
N
N
N
N
N
N
N
N
N
N
OH
Ar
OH
OH
NH
N
Compound 1 is the development compound identified
from the triazolopyridazine series18 and we sought to
identify alternative leads and intellectual property.
2,3,7-Trisubstituted pyrazolo[1,5-d][1,2,4]triazines 2 were
unique structures at the time we embarked on this strategy
although since then we have published on one such mole-
cule as a GABAA a5 selective inverse agonist for cogni-
tion enhancement.25 Herein we report on the synthesis
and SAR of 2,3,7-trisubstituted pyrazolo[1,5-d][1,2,4]tri-
azines as GABAA a3 selective agonists (Fig. 1).
N
N
NH
H
Ph
Ph
Ph
Ph
O
O
O
O
N
N
N
N
N
N
N
N
N
N
N
N
Scheme 2.
there was evidence for cyclisation in the mass spectrom-
eter to 8. A likely pericyclic mechanism for the thermal
cyclisation of 7 to give 8 is outlined in Scheme 2.
Starting from commercially available phenyltetronic acid
3, reaction with hydrazine hydrate in ethanol under reflux
for 10 days gave the 3-hydroxy pyrazole 4. (Scheme 1).
Alkylation at the 3-position of 4 with 3-chloromethyl-2-
methyl-1,2,4-triazole followed by oxidation of the pri-
mary alcohol with manganese dioxide gave the aldehyde
6. Condensation of 6 with (2-fluoro)benzhydrazide gave
7 which was cyclised to the target molecule 8 by heating
at 200 ꢁC in Dowtherm A for 30 h.
Compound 8 was evaluated in our standard biological
assays and was found to be a high affinity ligand at
GABAA receptors (Ki: a3 = 0.77 nM, a1 = 0.39 nM)
with functional selectivity favouring a3-containing
receptors (0.44 rel to CDZ) over a1-containing receptors
(0.18 rel to CDZ) as measured in the electrophysiologi-
cal assay.
In order to allow optimisation studies at the 2-(R1) and
3-(R2) positions, the versatile 3-bromo intermediate 14
was synthesised as described in Scheme 3. Reaction of
Compound 7 exists as two distinct tautomers in NMR
solution, the structure as drawn in Scheme 1 and the
tautomer (7a) in Scheme 2. On characterisation of 7
OH
NH
OH
NH
O
i
ii
O
N
N
F
82%
54%
N
N
HO
TsO
N N
N
HO
11
10
9
R3
N
60% iii,iv, v
N
N
R2
2
1
N
N
N
N
O
N
F
N
F
N
F
vii
O
vi
83%
N
N
Br
HO
N
N
R1
91%
N
N
N
TsO
HO
13
12
14
N
R1 = Heterocycle,
R2 = Aryl, Heteroaryl,
Alkyl or Cycloalkyl
R3 = Aryl, Heteroaryl
Scheme 3. Reagents and conditions: (i) NH2NH2ÆH2O, EtOH, reflux,
1 h; (ii) TsCl, Et3N, CH2Cl2, rt, 16 h; (iii) MnO2, CHCl3, reflux, 8 h;
(iv) 2-fluorobenzhydrazide, xylene, reflux, 1 h; (v) Dowtherm
A
(0.025 M), 180 ꢁC, 3 days; (vi) 4 N NaOH, dioxane–H2O, 60 ꢁC, 3 h;
(vii) Br2, AcOH, rt, 2.25 h.
Figure 1. New class of benzodiazepine receptor ligands (2).

3552
R. W. Carling et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3550–3554
hydrazine hydrate with tetronic acid (9) in refluxing eth-
anol for just 1 h gave the 3-hydroxy pyrazole 10.26 The
2-hydroxy group was protected with tosyl to give 11,
before oxidation of the primary alcohol, condensation
with (2-fluoro)benzhydrazide and subsequent cyclisation
at elevated temperature to give 12. Removal of the tosyl
group with sodium hydroxide in aqueous dioxane, fol-
lowed by bromination of 13 in acetic acid, gave 14.
N
N
F
N
N
The 2-position of 14 was alkylated with 3-(chlorometh-
yl)-2-methyl-1,2,4-triazole hydrochloride in the presence
of caesium carbonate in DMF and Suzuki or Stille
chemistry was used to elaborate the 3-position in high
yield as shown in Scheme 4.
N
ii
O
N
N
N
N
38
N
F
N
F
77%
iii
N
i
Br
N
Br
HO
N
Me
N
N
N
85%
O
N
N
14
F
S
N
91%
N
Me
Fluorinated and di-fluorinated phenyl groups (com-
pounds 16, 20 and 26–30) were introduced using the
route described in Scheme 1, starting from the appropri-
ate fluorophenyl tetronic acid. The other 3-substituted
phenyl analogues (Table 1) as well as all the 3-heteroaryl
analogues (Table 2) were prepared using palladium
catalysed couplings in a similar way to the heterocyclic
couplings described in Scheme 4. Optimisation studies
at the 7-position (R3) were easily carried out essentially
using the route outlined in Scheme 1 but starting with 2-
fluorophenyl tetronic acid and by using the appropriate
acylhydrazides in the penultimate step (compounds 38–
45, Table 3; and 46–49 and 51, Table 4). Compound 50
was made starting from phenyl tetronic acid as in
N
N
O
15
33
N
N
Me
N
Scheme 4. Reagents and conditions: (i) 3-(chloromethyl)-2-methyl-
1,2,4-triazole hydrochloride, Cs2 CO3; DMF, rt to 60 ꢁC, 25 h; (ii) 2-
(tributylstannyl)pyridine, Pd(PPh3)4, CuI, dioxane, 100 ꢁC, 18 h; (iii)
thiophene-3-boronic acid, Pd2dba3, P(t-Bu)3, Cs2CO3, dioxane,
80–90 ꢁC, 41 h.
Table 1. Effect of 3-aryl changes on a3 affinity and a1 and a3 efficacy
N
N
F
R
N
N
O
Table 2. Effect of 3-heteroaryl changes on a3 affinity and a1 and a3
efficacy
N
N
Me
N
N
Compound
R
Kia a3
(nM)
Efficacyb,c
Efficacyb,c
N
F
a1
a3
X
N
8
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
H
2-F
0.77
0.45
8.7
0.18
0.22
0.32
—
0.44
0.40
0.32
—
N
O
2-Cl
2-Me
2-CF3
3-F
23
N
>33
0.28
1.1
—
—
N
R
N
0.23
0.35
0.35
0.30
0.50
0.42
0.09
0.27
0.29
0.23
—
0.46
0.45
0.28
0.46
0.50
0.38
0.31
0.40
0.46
0.45
—
3-Cl
3-CN
3-CF3
Compound
X
Kia a3
(nM)
Efficacyb,c
Efficacyb,c
1.6
a1
a3
0.54
6.6
3-CH2OH
3-NH2
4-F
31
32
33
34
35
36
37
2-Thienyl
3-Thienyl
2-Furyl
0.10
0.10
0.11
1.4
0.01
À0.02
À0.09
0.45
0.12
0.21
0.16
0.56
0.52
0.19
—
14
6.3
1.5
2,3-F2
2,5-F2
2,6-F2
3,5-F2
2-Pyridyl
3-Pyridyl
4-Pyridyl
0.20
0.55
>33
0.98
0.14
>33
0.35
0.10
5-Pyrimidyl
—
a Ki values for binding to the BZ sites of stably expressed human
recombinant GABAA receptors with the composition a3b3c2. Inhi-
bition of the binding of 1.8 nM [3H]Ro15-1788 was measured and the
concentration required to inhibit binding by 50% (IC50) was con-
verted to a Ki value according to the Cheng–Prusoff equation.22 Data
shown are means of three to ten experiments.
b Modulation of chloride ion flux in cells expressing b3c2 plus either a1
or a3 produced by an EC20 equivalent concentration of GABA in the
presence of an approximate 1000 · Ki concentration of test com-
pound.23 Efficacy is expressed relative to the full agonist chlorodia-
zepoxide (relative efficacy = 1.0), from at least seven independent
experiments.
a Ki values for binding to the BZ sites of stably expressed human
recombinant GABAA receptors with the composition a3b3c2. Inhi-
bition of the binding of 1.8 nM [3H]Ro15-1788 was measured and the
concentration required to inhibit binding by 50% (IC50) was con-
verted to a Ki value according to the Cheng–Prusoff equation.22 Data
shown are means of three to ten experiments.
b Modulation of chloride ion flux in cells expressing b3c2 plus either a1
or a3 produced by an EC20 equivalent concentration of GABA in the
presence of an approximate 1000 · Ki concentration of test com-
pound.23 Efficacy is expressed relative to the full agonist chlorodia-
zepoxide (relative efficacy = 1.0), from at least seven independent
experiments.
c Efficacy measurement of effect of test compound on a current at
GABA EC20 using whole-cell patch-clamp electrophysiological
recording.14,24 Efficacy is expressed relative to the full agonist chlo-
rodiazepoxide (relative efficacy = 1.0), from at least seven indepen-
dent experiments.
c Efficacy measurement of effect of test compound on a current at
GABA EC20 using whole-cell patch-clamp electrophysiological
recording.14,24 Efficacy is expressed relative to the full agonist chlo-
rodiazepoxide (relative efficacy = 1.0), from at least seven indepen-
dent experiments.

R. W. Carling et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3550–3554
3553
Table 3. Effect of 7-aryl changes on a3 affinity and a1 and a3 efficacy
Table 4. Effect of 7-heteroaryl changes on a3 affinity and a1 and a3
efficacy
N
F
N
N
F
R
N
N
N
O
N
R
N
O
N
N
Me
N
N
N
Me
N
Compound
R
Kia a3 (nM) Efficacyb,c a1 Efficacyb,c a3
Compound
R
Kia a3 Efficacyb,c a1 Efficacyb,c a3
(nM)
16
38
39
40
41
42
43
44
45
2-F
3-F
0.45
1.2
0.22
0.38
0.36
0.42
0.52
0.29
0.45
0.37
À0.02
0.40
0.57
0.60
0.78
0.52
0.55
0.55
0.59
0.02
4-F
0.94
2.0
46
47
48
49
50d
51
3-Pyridyl 1.1
Pyrazinyl 2.7
0.15
0.03
0.16
0.18
2,4-F2
2,5-F2
2,6-F2
1.3
0.52
2-Furyl
3-Furyl
0.85
0.61
0.01
0.07
0.19
À0.12
0.19
2,3,6-F3 2.7
2,4,6-F3 2.6
2-Thienyl 1.6
cy-Propyl 0.36
À0.03
À0.08
À0.01
2-Cl
21
a Ki values for binding to the BZ sites of stably expressed human
recombinant GABAA receptors with the composition a3b3c2. Inhi-
bition of the binding of 1.8 nM [3H]Ro15-1788 was measured and the
concentration required to inhibit binding by 50% (IC50) was con-
verted to a Ki value according to the Cheng–Prusoff equation.22 Data
shown are means of three to ten experiments.
b Modulation of chloride ion flux in cells expressing b3c2 plus either a1
or a3 produced by an EC20 equivalent concentration of GABA in the
presence of an approximate 1000 · Ki concentration of test com-
pound.23 Efficacy is expressed relative to the full agonist chlorodia-
zepoxide (relative efficacy = 1.0), from at least seven independent
experiments.
a Ki values for binding to the BZ sites of stably expressed human
recombinant GABAA receptors with the composition a3b3c2. Inhi-
bition of the binding of 1.8 nM [3H]Ro15-1788 was measured and the
concentration required to inhibit binding by 50% (IC50) was con-
verted to a Ki value according to the Cheng–Prusoff equation.22 Data
shown are means of three to ten experiments.
b Modulation of chloride ion flux in cells expressing b3c2 plus either a1
or a3 produced by an EC20 equivalent concentration of GABA in the
presence of an approximate 1000 · Ki concentration of test com-
pound.23 Efficacy is expressed relative to the full agonist chlorodia-
zepoxide (relative efficacy = 1.0), from at least seven independent
experiments.
c Efficacy measurement of effect of test compound on a current at
GABA EC20 using whole-cell patch-clamp electrophysiological
recording.14,24 Efficacy is expressed relative to the full agonist chlo-
rodiazepoxide (relative efficacy = 1.0), from at least seven indepen-
dent experiments.
c Efficacy measurement of effect of test compound on a current at
GABA EC20 using whole-cell patch-clamp electrophysiological
recording.14,24 Efficacy is expressed relative to the full agonist chlo-
rodiazepoxide (relative efficacy = 1.0), from at least seven indepen-
dent experiments.
d Unsubstituted 3-phenyl group.
Scheme 1. For experimental details of the synthesis of all
the compounds described in this paper, please refer to
the patent literature.27 The a-methyl 1,2,4-triazolylm-
ethyloxy group at the 2-position was kept as a constant
in all the compounds in this communication since prec-
edent showed that in the structurally related triazolopy-
ridazine series, it was an absolute requirement for a3/a1
functional selectivity.18,28
nanomolar affinity at a3 receptors, is an antagonist at
a1 receptors and has a3 efficacy of 0.21 relative to the
full agonist CDZ. The 2-thiophene 31 and the 2-furan
33 also retain high affinity but have an inferior efficacy
profile. The 2- and 3-pyridyl analogues (34 and 35) show
nanomolar binding affinity at a3 receptors but both
have raised efficacy at a1 receptors. The 4-pyridyl deriv-
ative (36) retains subnanomolar a3 affinity but has insuf-
ficient functional selectivity, whilst the 5-pyrimidyl
compound 37 is significantly lower in binding affinity.
The o-fluoro 3-phenyl analogue 16 has essentially an
identical binding and efficacy profile to the prototype
molecule 8 (Table 1). However, the o-position of the
3-phenyl ring only tolerates small substituents since
significant loss of a3 affinity is observed with chloro,
methyl and in particular trifluoromethyl. The p-fluoro
analogue 26 loses an order of magnitude in binding
affinity but keeps functional selectivity for a3, whilst
the m-position of the 3-phenyl group tolerates a wider
range of substituents though polar groups lose affinity
and selectivity. 2,3-, 2,5- and 2,6-Difluoro substitution
(compounds 27, 28 and 29) is well tolerated but as with
all of the analogues in Table 1, efficacy at a1 is too high
with our requirement for an ideal compound being an
a1 antagonist and an a3 agonist.
Precedent within the triazolopyridazine series suggested
that large substituents on the 7-aryl ring would cause a
significant reduction in binding affinity and so only
the changes outlined in Table 3 were carried out. The
3- and 4- mono fluoro analogues 38 and 39 showed
increased efficacy at both a1 and a3 subtypes in compar-
ison to 16 and the prototype molecule 8 but kept a
window of selectivity. Difluoro and trifluoro substitu-
tion offered no advantage, with the 2,5-difluoro
analogue (41) in particular losing selectivity. Replacing
the 2-fluoro substituent with chloro (45) results in
reduced affinity, selectivity and efficacy.
Of the 7-heteroaryl changes carried out, the 2-furan (48)
and the 2-thiophene (50) have lower efficacy than 16 and
have a comparable affinity and efficacy profile to 32.
Of the 3-heteroaryl changes carried out, the most inter-
esting compound is the 3-thiophene 32, which has sub-

3554
R. W. Carling et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3550–3554
13. Yu, S.; He, X.; Ma, C.; McKernan, R.; Cook, J. M. Med.
Chem. Res. 1999, 9, 186.
14. Albaugh, P. A.; Marshall, L.; Gregory, J.; White, G.;
Hutchison, A.; Ross, P. C.; Gallagher, D. W.; Tallman,
J. F.; Crago, M.; Casella, J. V. J. Med. Chem. 2002, 45,
5043.
Other heterocycles such as 3-pyridyl (46), 3-pyrazinyl
(47) or 3-furyl (49) retained affinity but offered no
improvement in efficacy or functional selectivity. Inter-
estingly, the 7-cyclopropyl analogue (51) retained affini-
ty but lost considerable efficacy in comparison to 16.
15. Collins, I.; Moyes, C.; Davey, W. B.; Rowley, M.; Castro,
J. L.; Bromidge, F.; Quirk, K.; Atack, J. R.; McKernan,
R. M.; Thompson, S. A.; Wafford, K.; Dawson, G. R.;
Pike, A.; Sohal, B.; Tsou, N. N.; Ball, R. G. J. Med. Chem.
2002, 45, 1887.
16. Crawforth, J.; Atack, J. R.; Cook, S. M.; Gibson, K. R.;
Nadin, A.; Owens, A. P.; Pike, A.; Rowley, M.; Smith, A.
J.; Sohal, B.; Sternfeld, F.; Wafford, K.; Street, L. J.
Bioorg. Med. Chem. 2004, 14, 1679.
17. Carling, R. W.; Moore, K. W.; Street, L. J.; Wild, D.;
Isted, C.; Leeson, P. D.; Thomas, S.; O’Connor, D.;
McKernan, R. M.; Quirk, K.; Cook, S. M.; Atack, J. R.;
Wafford, K. A.; Thompson, S. A.; Dawson, G. R.; Ferris,
P.; Castro, J. L. J. Med. Chem. 2004, 47, 1807.
18. Carling, R. W.; Madin, A.; Guiblin, A.; Russell, M. G. N.;
Moore, K. W.; Mitchinson, A.; Sohal, B.; Pike, A.; Cook,
S. M.; Ragan, I. C.; McKernan, R. M.; Quirk, K.; Ferris,
P.; Marshall, G.; Thompson, S. A.; Wafford, K. A.;
Dawson, G. R.; Atack, J. R.; Harrison, T.; Castro, J. L.;
Street, L. J. J. Med. Chem. 2005, 48, 7089.
A novel synthesis of previously inaccessible 2,3,7-trisub-
stituted pyrazolo[1,5-d][1,2,4]triazines has been devel-
oped to identify the prototype 8 as a high affinity ligand
for the GABAA BZ binding site with functional selectivity
for agonism at a3-containing receptors over a1-contain-
ing receptors. The chemistry has been further developed
to enable efficient introduction of 2- and 3-substituents
as the last steps in the synthesis. The pyrazolo[1,5-
d][1,2,4]triazine series has produced compounds with
extremely high GABAA binding affinity some of which
show selective in efficacy for a3-containing subtypes over
a1-containing subtypes. The best compound identified
from this series is 32 which has high in vitro affinity
(0.1 nM), functional selectivity favouring a3 (0.21) over
a1 (À0.02), very good receptor occupancy (0.54 mg/kg
po)18 and good rat oral bioavailability (32%).
19. Goodacre, S. C.; Street, L. J.; Hallett, D. J.; Crawforth,
J. M.; Kelly, S.; Owens, A. P.; Blackaby, W. P.; Lewis,
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