Neurologically-active compounds

Details Neurologically-active compounds Neurologically-active compounds

1999-12-22

2003-10-14

Travers, Russell (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

Reexamination Certificate

active

06632806

ABSTRACT:

This invention relates to neurologically-active compounds, and to methods of use thereof. In particular the invention relates co methods of enhancing cognitive activity using compounds which are antagonists of GABA
C
receptors. Preferred compounds for use in the methods of the invention are TPMPA and analogues thereof, and novel compounds are disclosed.
BACKGROUND OF THE INVENTION
There are three major classes of GABA receptors in the central nervous system (CNS): GABA
A
, GABA
B
and GABA
C
receptors. The pharmacology of GABA
A
and GABA
B
receptors has been extensively investigated, but GABA
C
receptors have been only recognised recently, and their pharmacological potential is still unknown (Johnston, 1996b).
&ggr;-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system (CNS), and activates three major subtypes of GABA receptors, the GABA
A
, GABA
B
and GABA
C
receptors. GABA
A
receptors are ligand-gated Cl
−
channels which are inhibited by the alkaloid bicuculline (Johnston, 1996a). These are heterooligomeric receptors made up of &agr;, &bgr;, &ggr;, and &dgr; subunits. GABA
B
receptors are transmembrane receptors coupled to second messenger systems and Ca
2+
and K
+
channels via G-proteins. These receptors are not blocked by bicuculline, but are activated by (−)baclofen and 3-aminopropylphosphinic acid (CGP27492) and blocked by phaclofen and saclofen (Kerr and Ong, 1995).
GABA
C
receptors (sometimes called GABA
NANB
or r receptors) were first proposed when a series of conformationally restricted GABA analogues, including cis-4-aminocrotonic acid (CACA), that had bicuculline-insensitive depression actions on neuronal activity, showed no affinity for [
3
H]baclofen binding sites in rat cerebellar membranes (Drew et al, 1984). GABA
C
receptors with similar pharmacology were first found in neurons from rat retina (Feigenspan et al, 1993) and white perch retina (Qian et al, 1993). In rat retina, rod bipolar cells contain bicuculline-insensitive, baclofen-insensitive receptors that were activated by CACA (Feigenspan et al, 1993). These were detected by the co-application of GABA with 100 &mgr;M bicuculline to abolish the GABA
A
component (Feigenspan et al, 1993). In white perch retina, rod-driven horizontal cells (H4) and not bipolar cells showed GABA
C
receptor-like pharmacology. Application of GABA on bipolar cells showed rapid desensitisation, while on rod-driven horizontal cells, desensitisation was not observed (Qian et al, 1993). Subsequently, GABA
C
receptors were found on cone-driven horizontal cells in catfish (Dong et al, 1994) and bipolar terminals in tiger salamander (Lukasiewicz et al, 1994).
The expression of mRNA from bovine retina in
Xenopus oocytes
showed that GABA activated two distinct GABA receptors Both receptors activated Cl
−
currents. One was mediated by GABA
A
receptors and was blocked by bicuculline, and the other was mediated by GABA
C
receptors and was insensitive to both bicuculline and baclofen (Polenzani et al, 1991). Subsequently, two cDNAs that have 30-38% sequence identity with GABA
A
receptor subunits were cloned from human retinal mRNA (Cutting et al, 1991; 1992). These subunits have been termed r
1
and r
2
, and have 74% sequence identity (Cutting et al, 1991; 1992)
At least two major subtypes of GABA
C
receptors are now known, namely rho-1 and rho-2. As is known for other neurotransmitter receptor subtypes, different subtypes of GABA
C
receptors are likely so be involved in different aspects or nervous system function. As the rho-2 subunit is found in the hippocampus and neocortex, and these areas of the brain are important for memory, potent and selective agents for the rho-2 GABA
C
receptor are key compounds.
The species equivalents of the human r
1
and r
2
subunits have been cloned from rat (Enz et al, 1995). These show 88-99% homology with the respective human sequences. The use of PCR and in situ hybridisation have shown high expression of both the r
1
and r
2
subunits in rod bipolar cells. However, only the r
2
subunit is expressed in the CNS, particularly in the hippocampus and cortex (Enz et al, 1995). Recently, a third r subunit was cloned from rat retina cDNA (Ogurusu and Shingai, 1996). This subunit exhibits 63% and 61% sequence homology to the human r
1
and rat r
2
sequences respectively (Ogurusu and Shingai, 1996).
Expression of human r subunits in
Xenopus oocytes
generates homooligomeric GABA receptors with intrinsic Cl
−
channels. These receptor ion channels are activated by GABA and CACA, but are insensitive to bicuculline, (−)baclofen, barbiturates and benzodiazepines. They have been shown to be sensitive to picrotoxin, and have been classified as GABA
C
receptors (Cutting et al, 1991; 1992; Polenzani et al, 1991; Shimada et al, 1992; Kusama et al, 1993a; 1993b; Wang et al, 1994; Bormann and Feigenspan, 1995; Johnston, 1996b).
The most potent GABA
C
receptor agonists known so far are trans-4-aminocrotonic acid (TACA, K
D
=0.6 &mgr;M) and GABA (K
D
=1.7 &mgr;M) (Woodward et al, 1993). TACA, a conformationally restricted analogue of GABA in an extended conformation, is also a GABA
A
receptor agonist (Johnston, 1996a). CACA, a conformationally-restricted analogue of GABA in a folded conformation, has moderate partial agonist activity at GABA
C
receptors (K
D
=74 &mgr;M), and may be the most selective agonist for this receptor subtype (Johnston, 1996b).
Selective agonists and antagonists are needed to determine the physiological role of GABA
C
receptors and to provide more specific therapeutic agents with a lower risk of unwanted side-effects. GABA is a flexible compound, due to its rotation about the C2-C3 and C3-C4 bonds. It can exist in a range of low energy conformations (Johnston et al, 1978; Allan and Johnston, 1983). Two of these conformations have been restricted by the introduction of unsaturation in the form of a double bond at the C2-C3 position, and two compounds that represent these restricted conformations are CACA and TACA (Johnston et al, 1975). CACA and TACA have fewer degrees of rotational freedom than GABA, and can only rotate about the C3-C4 bond (Johnston et al, 1978; Allan and Johnston, 1983). CACA is a partially folded analogue of GABA. It has moderate activity at GABA
C
receptors expressed in
Xenopus oocytes
, and although its agonist activity is weak, it is to date the most selective agonist at these receptors, having minimal activity on GABA
A
and GABA
B
receptors (Johnston, 1996b). TACA is an extended analogue of GABA. It has potent agonist activity at GABA
C
receptors expressed in
Xenopus oocytes
; however, it is not selective, as it is also a potent GABA
A
receptor agonist (Johnston, 1996b).
Woodward et al (1993), using poly(A)
+
RNA from mammalian retina expressed in
Xenopus oocytes
; tested many GABA
A
and GABA
B
receptor agonists and antagonists to determine a pharmacological profile for GABA
C
receptors. From this study, it was found that the phosphinic and methylphosphinic analogues of GABA, which are known to be potent GABA
B
receptor agonists, were potent antagonists at GABA
C
receptors.
A series of GABA analogues was tested for agonist and antagonist activity at GABA
C
receptors, using poly(A)
+
. RNA from mammalian retina injected into
Xenopus oocytes
. Several potent GABA
C
receptor antagonists were identified, including (3-aminopropyl)methylphosphinic acid (CGP35024; K
B
=0.8 &mgr;M), 3-aminopropylphosphinic acid (CGP27492; K
B
=1.8 &mgr;M), and 3-aminopropylphosphonic acid (3-APA, K
B
=10 &mgr;M) (Woodward et al, 1993). These agents are not selective for GABA
C
receptors, as CGP35024 and CGP27492 are also very potent GABA
B
receptor agonists, while 3-APA is a GABA
B
receptor antagonist.
To date, only one specific GABA
C
receptor antagonist has been described. A more recently synthesised compound, 1,2,5,6-tetrahydropyridine-4-yl)methylphosphinic acid (TPMPA), does show potent and selectiv

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