Expert Opinion on Investigational Drugs

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GABAB receptor agonists and antagonists:

pharmacological properties and therapeutic
possibilities

SJ Enna

To cite this article: SJ Enna (1997) GABAB receptor agonists and antagonists: pharmacological
properties and therapeutic possibilities, Expert Opinion on Investigational Drugs, 6:10, 1319-1325,
DOI: 10.1517/13543784.6.10.1319

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 Editorial

Central & Peripheral Nervous Systems

GABAB receptor agonists and antagonists:

pharmacological properties and therapeutic possibilities
SJ Enna

γ-Aminobutyric acid (GABA), an inhibitory neurotransmitter, is

widely distributed throughout the brain and spinal cord. Two
major families of GABA receptors have been identified, GABAA
and GABAB. While much is known about the pharmacological
and molecular properties of GABAA receptors, it is only within
the last few years that potent and selective antagonists have
been developed for the GABAB site, and only within the past
few months that this receptor has been cloned. Thus, tools are
now available to define more fully the GABAB receptor in terms
of its biology and the therapeutic potential of manipulating this
site. Data suggest that, in addition to their established use as
muscle relaxants, GABAB receptor agonists possess analgesic
and antitussive properties, and may be useful for treating
bladder dysfunction. While there is less clinical data on GABAB
receptor antagonists, preclinical results indicate that they may
be of value in treating absence epilepsy, cognitive dysfunction
and, possibly, pulmonary and intestinal disorders. However, for
this potential to be fully exploited, it is necessary to identify and
characterise molecularly and pharmacologically distinct GABAB
receptor subtypes.

Keywords: analgesia, cognition, epilepsy, GABA, GABAB, receptors

Exp. Opin. Invest. Drugs (1997) 6(10):1319-1325

1. Introduction ing the benzodiazepines and barbiturates [1,2]. Mo-

GABA is an inhibitory neurotransmitter found through-
out the neuroaxis and in some peripheral tissues.
Given its concentration, widespread distribution in the
brain and spinal cord, and the fact that virtually all
neurones can be hyperpolarised by GABA, it was
believed initially that side-effects would preclude the
development of GABAergic drugs because they would,
presumably, modify virtually all central nervous system
functions. This concept changed drastically with the
discovery that GABA receptors are the primary site of
action for a number of clinically useful agents, includ-
lecular cloning experiments revealed that this site,
termed the GABAA receptor, is composed of five
separate subunits [3]. Given the array of subunits and
subunit combinations, the potential number of
molecularly distinct GABAA receptors is quite large [3].
Regardless of their subunit composition, GABAA re-
ceptors are pentameric structures comprising a ligand-
gated chloride ion channel. Thus, it may one day be
possible to pharmacologically manipulate individual
GABAA receptors in particular brain regions and, per-
haps, in individual neurones, based on their distinct
molecular properties. The discovery of GABAB sites

1319
1997 © Ashley Publications Ltd. ISSN 1354-3784
1320 GABAB receptor agonists and antagonists - Enna
Figure 1: Selected GABAB agonists.
O
O sity of GABA receptors in general, and GABAB
H2N P CH
H2N P H
OH
OH
CGP 27492 CGP 35024
SKF 97541
Cl
O
H2N P CHF
OH
2 tested, it was not until the carboxylic acid portion of
O
H GABA was replaced by phosphinic acid residues that
H2N
CGP 47656 (R)(-)-Baclofen
adds to the diversity of GABA receptors. Unlike inot-
ropic GABAA sites, GABAB receptors are seven trans-
membrane spanning G-protein coupled entities.
Early attempts to manipulate the GABA receptor sys-
tem lead to the development of β-p-chlorophenyl-
GABA (baclofen) as a potential GABA receptor agonist
(Figure 1). Since GABA itself does not cross the
blood-brain barrier it was hoped that attachment of a
halogenated phenyl ring would provide lipophilicity
sufficient to facilitate diffusion of the molecule into the
brain. While this manoeuvre yielded a systemically
active compound that causes sedation and muscle
relaxation, it was discovered that baclofen does not
interact with the GABAA receptor site [4,5]. Years later,
while studying neurotransmitter release mechanisms,
Bowery et al. discovered that GABA inhibits the
evoked release of a number of neurotransmitters from
nerve terminals and that this effect is not blocked by
GABAA receptor antagonists, although it is mimicked
by baclofen [6,7]. Moreover, unlike the GABAA recep-
tor, agonist affinity for the baclofen-sensitive site was
found to be influenced by guanyl nucleotides, with
activation modifying cyclic AMP formation, as well as
calcium and potassium transport across neuronal
membranes [8-13]. Given these differences between
the baclofen-activated and GABAA sites, the former
was designated a GABAB receptor [8].
To characterise this site further, efforts were made to
design GABAB receptor antagonists and to clone the
gene for this receptor. Although a host of new GABAB
receptor agonists and antagonists have been synthe-
sised and tested during the past decade, it is only
recently that the receptor was cloned [14-18]. These
© Ashley Publications Ltd. All rights reserved.
advances have led to a better definition of the GABAB
receptor and have helped define the therapeutic po-
tential of compounds that interact with this site. Now
that the receptor has been cloned, the tempo of
discovery may increase further, resulting in new in-
sights about the biological and pharmacological diver-
3 receptors in particular.
2. GABAB receptor agonists
Baclofen, the prototypical GABAB receptor agonist,
has an affinity for the receptor similar to GABA (Figure
1, Table 1). While many baclofen analogues were
OH
significantly more potent and selective agonists were
discovered [15,19]. Included in this group are
CGP 47656, which may be a partial agonist for this site
[20], as well as the full agonists CGP 35024 (SKF 97541)
and CGP 27492, which have affinities equal to, or
greater than, baclofen (Figure 1 and Table 1). Given
its relatively high affinity, CGP 27492 was tritiated and
used for labelling the GABAB receptor [15].
Detailed structure-activity studies revealed that, with a
few exceptions, unsubstituted phosphinic acid ana-
logues and methylphosphinic acid derivatives are po-
tent GABAB receptor agonists [15]. Moreover, whereas
addition of an alkyl group on the 3-aminopropyl
side-chain decreases affinity for the GABAB site, 2-hy-
droxy substitution, or the addition of p-chlorophenyl
at this position, yields potent agonists.
Activation of GABAB receptors in brain and peripheral
organs inhibits the evoked release of a number of
neurotransmitters [21]. The effect in the periphery led
to speculation that GABAB agonists may be of thera-
peutic value in treating intestinal, urinary bladder and
pulmonary disorders. Indeed, it has been found that
many of the effects observed in these tissues are due
to GABAB receptor-mediated inhibition of acetyl-
choline release from autonomic ganglia. For example,
SKF 97541 (CGP 35024) inhibits cholinergically-medi-
ated bronchoconstriction in guinea-pig lung [22]. It has
also been suggested that GABAB agonists have antitus-
sive properties [23].
Administration of GABAB agonists, including baclofen
and CGP 44532, which is 2-hydroxy substituted CGP
35024 (Figure 1), produces analgesia in acute and
chronic pain models [24-27]. This response is due, in
part, to GABAB receptor-mediated inhibition of sub-
stance P release from primary afferent terminals which,
in turn, modifies neurokinin-1 receptor levels in the
dorsal horn, decreasing the transmission of pain im-
pulses. While GABAB agonists alleviate the formalin-
Exp. Opin. Invest. Drugs (1997) 6(10)
 Central & Peripheral Nervous Systems - Editorial 1321

Table 1: Characteristics of GABAB receptor agonists and antagonists.

Compound Inhibition of GABAB Reported properties and uses Reference

receptor binding
§
(IC50 nM)
Agonists
CGP 27492 5 Tritiated form used for GABAB receptor binding assay [15]
CGP 35024 (SKF 97541) 16 Inhibits cholinergically-mediated bronchoconstriction in [22]
guinea-pig
GABA 17 Endogenous neurotransmitter for the GABAB receptor
(R)(-)-Baclofen 32 Prototypical GABAB receptor agonist, skeletal muscle
relaxant
CGP 47656 89 Partial agonist at GABAB receptors [15]
Antagonists
CGP 64213 1 Iodinated form used to identify GABAB receptors during [14]
expression cloning
CGP 71872 1 Iodinated form used as a photoaffinity label to identify [14]
GABAB receptors in rat brain membranes
CGP 54626 4 Tritiated form used for GABAB receptor binding assay [39]
CGP 55845 6 Enhances evoked release of GABA and glutamate from rat [35]
spinal cord tissue
CGP 54062 10 Mixture of diastereoisomers [39]
CGP 52432 55 Enhances evoked release of GABA and glutamate from rat [35]
spinal cord tissue
SCH 50911 1000 Blocks absence seizures in animal models [36]
CGP 46381 5000 Blocks absence seizures in animal models [38]
CGP 35348 27,000 Blocks absence seizures in animal models [37]
CGP 36742 38,000 Blocks absence seizures in animal models and enhances [38,40]
cognition in rats, mice and monkeys
§ 3 3 3
Displacement assays conducted using rat brain membranes with [ H]-baclofen, [ H]-GABA or [ H]-27492 as the labelling
ligand [15,16,39].

induced late-phase pain response, administration of a
GABAB receptor antagonist alone does not enhance
pain, suggesting that endogenous GABA systems are
not active under these conditions. The effect of GABAB
agonists on substance P release and neurokinin recep-
tor expression in the spinal cord is similar to that
observed with morphine [28].
3. GABAB receptor antagonists
Once GABAB receptors were identified, efforts were
immediately undertaken to design antagonists for this
site. Initial attempts yielded phosphonic and sulfonic
acid analogues of baclofen as well as 3-benzo[b]
furan-2-yl-GABA derivatives, all of which have rela-
tively low affinities for the receptor and are ineffective
following systemic administration [29-32]. Structure-ac-
tivity studies with phosphinic GABAB receptor agonists
revealed that ethylphosphinic acid, and higher homo-
logues, are receptor antagonists (Figure 2; [16]). While
the initial members of this group, such as CGP 36742,
CGP 35348 and CGP 46381, displayed relatively low
affinities (µM) for the GABAB receptor (Figure 2,
Table 1), many were useful since they are active
following systemic administration [17]. A dramatic in-
crease in receptor affinity for phosphinic acid antago-
nists was noted when certain benzyl substituents were
placed on the nitrogen. Thus, compounds such as CGP

© Ashley Publications Ltd. All rights reserved. Exp. Opin. Invest. Drugs (1997) 6(10)
1322 GABAB receptor agonists and antagonists - Enna

Figure 2: Selected GABAB receptor antagonists.

O O O
O COOH
H2N P O H2N P H2N P
HO O HO N
HO H

CGP 35348 CGP 36742 CGP 46381 SCH 50911

Cl Cl Cl
O OH O OH O
H H H
N P O N P N P
Cl Cl Cl
HO HO HO
O

CGP 52432 (R,S),(S) CGP 54062 CGP 54626

(S),(S) CGP 55845

125
COOH I COOH
N3 OH
OH O OH O
H H H H
N P N N P N 125
I
HO HO
O OH O

[ 125I]-CGP 71872 [ 125I]-CGP 64213

52432, CGP 54062, and CGP 54626 display IC50 values
in the low nM range as inhibitors of GABAB receptor
binding (Figure 2, Table 1). Moreover, addition of a
substituted phenylpropionylamino (CGP 64213) or
benzoylamino (CGP 71872) moiety on the phosphinic
acid side-chain yielded antagonists with high affinities
(~ 1 nM) for the receptor and which can be labelled
with 125I (Figure 2, Table 1). In addition, CGP 71872
is used as a photoaffinity label for the GABAB site [14].
Using a different synthetic approach it was discovered
that 2,5 disubstituted-1,4-morpholines, such as SCH
50911, as well as thiomorpholines, have GABAB recep-
tor antagonist properties (Figure 2) [33]. While mem-
bers of this series are orally active, their affinities for
the GABAB receptor are relatively low in comparison
with some of the phosphinic acid derivatives (Table
1). Because of their structure, these compounds are
particularly useful pharmacophores for modelling the
GABAB receptor [34].
The GABAB receptor antagonists are active in a variety
of biochemical and behavioural tests. Thus, both CGP
55845 and CGP 52432 enhance the evoked release of
neurotransmitter from rat spinal cord tissue and block
baclofen-induced inhibition of this response, indicat-
ing that this transmitter release is regulated by presy-
naptic GABAB receptors [35]. Moreover, SCH 50911
blocks the inhibitory response to baclofen in isolated
guinea-pig trachea and the antitussive effect of
baclofen in both guinea-pigs and cats [33]. In addition,
SCH 50911, CGP 46381, CGP 35348 and CGP 36742 all
block absence seizures in a variety of animal models,
and CGP 36742 significantly improves cognitive per-
formance in rodents and primates [36-38,40].
4. Therapeutic applications
Baclofen has been employed for decades as a muscle
relaxant to treat spasticity and skeletal muscle rigidity,
with sedation being the major side-effect associated
with its use. Although baclofen displays significant
analgesic activity in laboratory animals, it has not been
found to be clinically useful in this regard. While the
reasons for this difference between species are un-
known, it is possible that tolerance develops rapidly
to the analgesic effect or that the analgesic dose in
humans is far above that necessary for profound
sedation and skeletal muscle relaxation. If, as seems
likely, there are pharmacologically and functionally
distinct GABAB receptors, it may be possible to de-
velop a receptor agonist with greater selectivity for
sites mediating analgesic responses, as compared to
those responsible for sedation and muscle relaxation

© Ashley Publications Ltd. All rights reserved. Exp. Opin. Invest. Drugs (1997) 6(10)

[20,41,42]. Such an agent may be particularly useful for
treating types of back pain that would benefit from a
combined muscle relaxant/analgesic.
As there are GABAB receptors on peripheral neurones
there is speculation that antagonists may be of benefit
in treating a variety of conditions, including asthma,
bowel and bladder dysfunction [21]. However, until
GABAB agonists selective for peripheral receptors are
identified, it may be difficult to demonstrate the supe-
riority of this approach over current therapies.
There is a great deal of interest in identifying therapeu-
tic uses for GABAB receptor antagonists, given their
novel mechanism of action. Data suggest they may be
of value for treating a variety of neurological and
psychiatric conditions, including absence epilepsy and
cognitive impairments. Based on their neurochemical
effects, it is possible they may be of value in treating
anxiety and depression, and in protecting the brain
from neuronal damage associated with ischaemia [21].
5. Future prospects
The discovery of GABAB receptors has opened new
possibilities for the development of chemically and
mechanistically novel therapeutic agents for the treat-
ment of conditions ranging from asthma to memory
impairment. While significant progress has been made
regarding the chemistry and biology of this system,
much work remains to exploit these findings. In
particular, it is crucial to determine whether there are
pharmacologically distinct GABAB receptors. Although
biochemical studies with GABAB agonists and antago-
nists suggest the existence of such sites, and experi-
ence with other neurotransmitter receptors predicts the
presence of multiple subtypes, it will be difficult to
assess fully the therapeutic benefit of GABAB receptor
agonists and antagonists until there are definitive data,
in this regard. With the recent cloning of a GABAB
receptor [14], it should be possible to address this issue
directly. Indeed, it is notable that what appears to be
a second GABAB receptor has been cloned which
shares virtually no sequence homology and which
displays a somewhat different localisation in brain and
immunoreactivity than the receptor cloned earlier [43;
Kenya Kuriyama, Personal communication].
While it seems likely that GABAB antagonists, like
GABAA agonists, will yield clinical benefits by their
direct action in the central nervous system, it is ques-
tionable whether either type of agent will be of value
in treating dysfunctions of peripheral organs. Thus,
while pharmacologically responsive GABAB receptors
are located in peripheral organs and tissue, there is
© Ashley Publications Ltd. All rights reserved.
Central & Peripheral Nervous Systems - Editorial 1323
little evidence yet to suggest that these sites are of
physiological consequence.
The development of GABAB receptor antagonists, and
the cloning of this receptor, may herald the arrival of
a new class of drugs. While the therapeutic possibilities
are numerous given their mechanism of action, clinical
data are necessary to provide an appropriate perspec-
tive for their use.
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SJ Enna
Department of Pharmacology, Toxicology and Therapeutics, Univer-
sity of Kansas, Medical School, 3901 Rainbow Boulevard, Kansas
City, Kansas 66160, USA
(Tel: +1 913 588 7500; Fax: +1 913 588 7501;
Email: senna@kumc.edu)

© Ashley Publications Ltd. All rights reserved. Exp. Opin. Invest. Drugs (1997) 6(10)