Current
Topics in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 6, Number 10, 2006
Contents
GABA and Glutamate as Targets in Medicinal Chemistry
Guest Editor: Dr. Julianna Kardos
Editorial Pp. 927-928
Glial Modulation of GABAergic and Gluergic
Neurotransmission Pp 929-934
Arne Schousboe and Helle S. Waagepetersen
[Abstract]
Extracellular Level of GABA and Glu: In Vivo
Microdialysis-HPLC Measurements Pp. 935-940
Gabriella Nyitrai, Katalin A. Kékesi and Gábor
Juhász
[Abstract]
Nonsynaptic Receptors for GABA and Glu Pp.
941-948
E. Sylvester Vizi and Arpad Mike
[Abstract]
Glutamate as a Modulator of Embryonic and Adult Neurogenesis
Pp. 949-960
Katalin Schlett
[Abstract]
Trophic Effect of Glutamate Pp. 961-968
Robert Balazs
[Abstract]
Functional Significance of Co-Localization of GABA
and Glu in Nerve Terminals: A Hypothesis Pp. 969-973
Jozsef Somogyi
[Abstract]
Co-Existence of GABA and Glu in the Hippocampal
Granule Cells: Implications for Epilepsy Pp. 975-978
Rafael Gutiérrez and Uwe Heinemann
[Abstract]
Co-Existence of GABA and Glu Transporters in
the Central Nervous System Pp. 979-988
Gianni Bonanno, Luca Raiteri, Silvio Paluzzi, Simona Zappettini,
Cesare Usai and Maurizio Raiteri
[Abstract]
Role for GABA and Glu Plasma Membrane Transporters
in the Interplay of Inhibitory and Excitatory Neurotransmission
Pp. 989-995
László Héja, Kinga Karacs and Julianna
Kardos
[Abstract]
Potassium Channels
Guest Editor: Dr. Vincenzo Calderone
Editorial Pp. 997-998
Kv7
Channels: Function, Pharmacology and Channel Modulators
Pp. 999-1023
William Dalby-Brown, Henrik H. Hansen, Mads P.G. Korsgaard,
Naheed Mirza and Søren-P Olesen
[Abstract]
Pharmacological Roles of the Large-Conductance Calcium
Activated Potassium Channel Pp. 1025-1030
Sheng-Nan Wu, Adonis Z. Wu and Ming-Wei Lin
[Abstract]
Structure-Activity Relationships of KATP
Channel Openers Pp. 1031-1047
Raimund Mannhold
[Abstract]
From Cromakalim to Different Structural Classes of
KATP
Channel Openers Pp. 1049-1068
Violetta Cecchetti, Oriana Tabarrini and Stefano Sabatini
[Abstract]
Abstracts
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Editorial
The inhibitory γ-aminobutyrate
(GABA) and the excitatory glutamate (Glu) are physiologically
and therapeutically important major signaling amino acids
within the brain. A strong interest in the drug discovery
community is directed to interplaying GABAergic and
Gluergic processes, as reflected in the large number
of publications devoted to this subject from the 1990’s.
In this issue of Current Topics in Medicinal Chemistry,
a selection of reviews on the recent developments in this
area is presented by researchers who have been active in the
field over many years. The topic of this issue is “GABA
and glutamate as targets in medicinal chemistry”,
with emphasis on glial-neuronal metabolic coupling, synaptic
vs. nonsynaptic and direct vs. indirect
co-signaling performed by GABA and/or Glu and the elucidation
of its physiological and pathological significance. Several
lines of functional and analytical evidence are reviewed which
cover co-existence of GABA and Glu within the synapse and
nonsynaptically. In this way, medicinal chemists have an updated
survey of the fundamentals of the complex problem of therapeutic
intervention associated with signaling by GABA and/or Glu.
The first contribution in this issue describes the function
of astroglia in the modulation of availability, release and
clearance of Glu and GABA within the central nervous system
(CNS). Arne Schousboe and Helle Waagepetersen give an overview
of the metabolic coupling between neurons and astroglia. The
GABA-Glu-Gln cycle ramifies astroglia and neurons at the expense
of the tricarboxilic acid cycle involving the activation of
astroglial Glu transporters. Specific strategy aimed at inhibiting
terminal GABA transporter subtype GAT1 has been successfully
applied in the development of the antiepileptic tiagabine.
The second review by Gabriella Nyitrai et al discusses
and evaluates methodological details and problems associated
with brain tissue microdyalisis. These in vivo measurements
are very important for monitoring changes in the extracellular
level of GABA and Glu under control and pathological conditions
such as ischemia and epilepsy. Reflecting extracellular concentrations,
the alterations of the amount of GABA and Glu in dyalisate
samples independent of neuronal activity precipitate a role
for glia in nonsynaptic communication.
The third review by Sylvester Vizi and Árpád
Mike investigate whether the archetypical synaptic neurotransmitters
GABA and Glu can operate via nonsynaptic transmission.
The authors collect evidence for different forms of nonsynaptic
transmission performed by the extrasynaptic GABA and Glu receptors
(GluRs). In the light of recent progress in the field theoretical
predictions of the concept of nonsynaptic transmission have
also been investigated. Extrasynaptic receptors and the ambient
neurotransmitters or drugs are expected to interact with higher
affinity. This feature may enable extrasynaptic receptors
to serve useful pharmacological targets.
Highlighted by Katalin Schlett, proliferative effects should
be distinguished from those which affect cell fate commitment
and/or survival. Glu actions on neurogenesis show distinct
differences in the developing and adult brain. Glu acts nonsynaptically
on dividing progenitors and can influence proliferation and
neuronal commitment. Pathological conditions including ischemia,
epilepsy and stress induce cell loss in the brain providing
a clue for therapeutic interventions aimed at enhancing neuronal
replacement.
Rewived by Robert Balazs, GluR activation may directly initiates
a cascade of events primarily involving Ca2+ ion-mediated
signaling and consecutive gene expression changes. Indirect
effects of GluR stimulation are due to the production and
release of neurotrophic factors, such as brain-derived neurotrophic
factor and also involve glia-neuronal interaction. Neuronal
loss can occur during development as well as in the adult
brain. Contrasting physiological and excessive stimulations,
usually associated with either trophic effects promoting neuronal
plasticity or neurotoxicity, respectively, may compromise
the therapeutic manipulation of GluRs.
Salient features of the co-transmission by GABA and Glu in
neural signaling are reviewed by József Somogyi. Several
brain areas, including granule cells of the Dentate Gyrus,
hippocampal mossy fibre terminals and their termination zone
in the CA3 subfield, retina, brain stem and spinal cord are
highlighted. The vesicular Glu (VGLUT3) and GABA (VIAAT) transporters
are functionally compatible making possible package and release
of Glu and GABA from the same terminals. His new hypothesis
on combinatorial neural code gives a possible reason for the
functional significance of co-transmission by GABA and Glu
in nerve terminals.
Rafael Gutiérrez and Uwe Heinemann highlight the granule
cells of the Dentate Gyrus whereby plastic changes
involving GABA and Glu do prominently occur. The presence
(and release) of GABA suggests that dentate granule cells
can also function as inhibitory cells. Markers of GABAergic
phenotype in granule cells, including GABA, the enzyme for
its synthesis and the membrane and vesicular transporters
are all up-regulated after epileptic seizures. The emergent
monosynaptic GABA receptor-mediated transmission in the mossy
fiber synapse restrains excitation and performs antiepileptic
and neuroprotective actions.
The concept of heterotransporters and its functional significance
are reviewed by Gianni Bonanno et al. Co-localization
of homotransporters and of transporters that can selectively
take up transmitters/modulators originating from neighboring
structures (heterotransporters) has been shown to occur within
the same axon terminal in several neuronal phenotypes and
brain areas. Release of Glu induced by the type GAT1 heterotransporter
activation takes place by reversal of the Glu homotransporter
and by anion channel opening. GABA-induced Glu release in
spinal cord is dramatically enhanced in a transgenic mouse
model of amyotrophic lateral sclerosis.
Finally, László Héja et al collect
emerging lines of evidence - partly reviewed in this thematic
issue - on interplaying GABAergic and Gluergic
transmission possibly involving the plasmamembrane transporters
of GABA and Glu. Although the nature of interplaying GABA
and Glu transport processes is far from being understood,
future mechanistic studies may provide a specific strategy
aimed at stimulating Glu transport.
I wish to thank Dr. Allen B. Reitz for the invitation to be
the Guest Editor of this thematic issue, and all of the contributors
devoting their valuable time to this issue. This work was
supported by grants Center of Excellence on Biomolecular Chemistry
QLK2-CT-2002-90436, Transporter Explorer AKF-050068 and MediChem2
1/A/005/2004 NKFP.
Dr. Julianna Kardos
Department of Neurochemistry
Institute of Biomolecular Chemistry
Chemical Research Center
Hungarian Academy of Sciences
Pusztaszeri út 59-67,
H-1025 Budapest,
Hungary
E-mail: jkardos@chemres.hu
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Glial Modulation of GABAergic and Gluergic
Neurotransmission
Arne Schousboe and Helle S. Waagepetersen
Function of astroglia in the modulation of availability,
release and clearance (inactivation) of Glu and GABA within
the central nervous system is reviewed. Net synthesis of Glu
through Gln synthethase exclusively localized in astrocytes
can only occur by a metabolic coupling between neurons and
astrocytes. Two (GLAST and GLT-1) of the five Glu transporters
cloned preferentially expressed in astrocytes perform the
astroglial Glu uptake of very high capacity. Moreover, astrocytes
have been shown to mediate Glu release by a mechanism mimicking
vesicular release. Biosynthesis of GABA in neurons is brought
about by decarboxylation of Glu catalyzed by a pyridoxal phosphate
requiring enzyme (GAD) that exists in two isoforms (GAD65
and GAD67) exhibiting different subcellular localization and
regulatory properties. Detailed studies of GABA synthesis
in GABAergic neurons using 13C NMR spectroscopy
have provided evidence for direct involvement of the tricarboxylic
acid cycle. Synaptically released GABA taken up into surrounding
astrocytes is converted to either CO2 or Gln. Two
reports on the release of GABA in rat dorsal root ganglia
indicated that glial cells may perform GABA release as well.
Gln formed from GABA in astrocytes can be transferred to GABAergic
neurons and subsequently converted to GABA. Inhibition of
either degradation or clearance of GABA has been successfully
applied in the development of antiepileptics such as vigabatrin
or tiagabine. So far, no specific strategy has been developed
aimed at stimulating Glu transport.
[Back to top]
Extracellular Level of GABA and Glu: In Vivo
Microdialysis-HPLC Measurements
Gabriella Nyitrai, Katalin A. Kékesi and Gábor
Juhász
In spite of several studies showing specific physiological
functions of changes in the extracellular level of the major
excitatory and inhibitory transmitters, Glu and GABA within
the brain ([Glu]EXT,
[GABA]EXT)
the exact origin (neuronal vs. astroglial, synaptic
vs. extrasynaptic) of Glu and GABA present in dialysate
samples is still a matter of debate. For better understanding
the significance of in vivo microdialysis data, here
we discuss methodological details and problems in addition
to regulation of [Glu]EXT
and [GABA]EXT.
Changes in [Glu]EXT
and [GABA]EXT
under pathological conditions such as ischemia and epilepsy
are also reviewed. Based on recent in vivo microdialysis
data we argue that ambient [Glu]EXT
and [GABA]EXT
may have a functional role. It is suggested that specific
changes in concentrations of Glu and GABA in dialysate samples
together with their alterations independent of neuronal activity
indicate the involvement of Glu and GABA in the information
processing of the brain as essential signaling molecules of
nonsynaptic transmission as well. Since various drugs are
able to interfere with extrasynaptic signals in vivo,
studying the extracellular cell-to-cell communication of brain
cells represents a new aspect to improve drugs modulating
Gluergic as well as GABAergic neurotransmission.
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Nonsynaptic Receptors for GABA and Glu
E. Sylvester Vizi and Arpad Mike
The concept of nonsynaptic communication between neurons,
once a heretic idea, has become a self-evident fact during
the almost forty years since its original discovery [1]. In
this review we investigate whether the archetypical synaptic
transmitters of the central nervous system, Glu and GABA,
can operate via nonsynaptic transmission. While experimental
data supporting the general concept of nonsynaptic transmission
has been progressively accumulating during these years, most
of the evidence regarding nonsynaptic transmission by Glu
and GABA are results of the last decade. In this paper we
collect evidence for different forms of nonsynaptic transmission
by the Gluergic and GABAergic system. We
investigate two theoretical predictions of the concept of
nonsynaptic transmission in the light of recent progress in
the field: i) since extrasynaptic receptors experience
a lower concentration of agonist, they are likely to have
higher affinity for the agonist ii) extrasynaptic
receptors are expected to be more important pharmacological
targets.
[Back to top]
Glutamate as a Modulator of Embryonic and Adult Neurogenesis
Katalin Schlett
It has been widely accepted that neurogenesis continues
throughout life. Neural stem cells can be found in the ventricular
zone of the embryonic and in restricted regions of the adult
central nervous system, including subventricular and subgranular
zones of the hippocampal dentate gyrus. The network of signaling
mechanisms determining whether neural stem cells remain in
a proliferative state or differentiate is only partly discovered.
Recent advances indicate that glutamate (Glu), the predominant
excitatory neurotransmitter in mature neurons, can influence
immature neural cell proliferation and differentiation, as
well.
Despite many similarities, Glu actions on neurogenesis in
the developing and adult brain show distinct differences and
are far from being clear. Due to alterations of Glu transport
mechanisms, extracellular Glu level is high in the embryonic
CNS. Glu acts non-synaptically on dividing progenitors either
by directly activating ionotropic and/or metabotropic Glu
receptors or can influence other cells which are located in
the vicinity of proliferating cells and produce molecules
regulating neural precursor cell proliferation by other mechanisms.
Due to the complexity of signaling pathways and to regional
differences in neural precursors, Glu can influence proliferation
and neuronal commitment as well, and acts as a positive regulator
of neurogenesis.
Brain injuries like ischemia, epilepsy or stress lead to severe
neuronal death and additionally, influence neurogenesis, as
well. Glu homeostasis is altered under these pathological
circumstances, implying that therapeutic treatments mediating
Glu signaling might be useful to increase neuronal replacement
after cell loss in the brain.
[Back to top]
Trophic Effect of Glutamate
Robert Balazs
During development, Glu receptors and N-methyl-D-aspartate
receptors in particular initiate a cascade of signal transduction
events and gene expression changes primarily involving Ca2+
ion-mediated signaling induced by activation of either Ca2+
ion-permeable receptor channels or voltage-sensitive Ca2+
ion channels. The consecutive activation of major protein
kinase signaling pathways, such as Ras-MAPK/ERK and PI3-K-Akt,
contributes to regulation of gene expression through the activation
of key transcription factors, such as CREB, SRF, MEF-2, NF-κB.
Metabotropic Glu receptors can also engage these signaling
pathways and this may be mediated, in part, by transactivating
receptor tyrosine kinases. Indirect effects of Glu receptor
stimulation are due to the production and release of neurotrophic
factors, such as brain derived neurotrophic factor and also
involve glia-neuronal interaction through Glu-induced release
of trophic factors from glia. The trophic effect of Glu receptor
activation is developmental stage-dependent and may play an
important role in determining the selective survival of neurons
that made proper connections. During this sensitive developmental
period interference with Glu receptor function may lead to
widespread neuronal loss. However, NMDA receptor blockade-induced
neurodegeneration can also occur in the adult brain. Depending
on the stimulus strength, Glu receptors mediate biphasic effects.
In addition to synaptic transmission, physiological stimulation
of Glu receptors can mediate trophic effects and promote neuronal
plasticity. Excessive stimulation is neurotoxic. Attention
must, therefore, be paid to these features, when therapeutic
manipulation of excitatory amino acid receptors is considered
in the clinical setting.
[Back to top]
Functional Significance of Co-Localization of GABA
and Glu in Nerve Terminals: A Hypothesis
Jozsef Somogyi
Salient features of the co-transmission by GABA and Glu in
neural signaling are summarized. Experimental data have been
accumulating which demonstrate; i) GABA-immunoreactivity
in and GABA-release from constitutively Gluergic
hippocampal mossy fibre terminals, ii) plasticity
of the GABAergic phenotype of constitutively Gluergic
granule cells of the Dentate Gyrus, iii)
expression of GABAAreceptor
γ3
subunit in the mossy fibre termination zone in the CA3 subfield,
iv) co-labeling of terminals for GABA and Glu in
the retina, brain stem and spinal cord, and v) functional
compatibility of vesicular Glu (VGLUT3) and GABA (VIAAT) transporters.
It is not clear, however, whether or not Glu and GABA are
released from the same terminals, and packaged in the same
vesicles. Using multiple transmitters neurons may serve to
reduce the metabolic cost and errors of signaling.
[Back to top]
Co-Existence of GABA and Glu in the Hippocampal Granule
Cells: Implications for Epilepsy
Rafael Gutiérrez and Uwe Heinemann
The granule cells of the Dentate Gyrus are one of
the most exciting and intriguing cells in the central nervous
system. Besides containing and releasing Glu, they have been
shown to contain and release peptides (somatostatin, neuropeptide
Y, neurokinin B, cholecystokinin, dynorphin, enkephalin),
Zn++ ion, and brain-derived neurotrophic factor
(BDNF). The recent addition of GABA to this list suggests
that these cells can also function as inhibitory cells. Indeed,
evidence has been presented of co-localization of all markers
of the GABAergic phenotype in granule cells: GABA,
the enzyme for its synthesis (Glu decarboxylase) and the membrane
and vesicular transporters of GABA. These markers of the GABAergic
phenotype are up-regulated after epileptic seizures. When
this occurs, monosynaptic GABA receptor-mediated transmission
emerges in the mossy fiber synapse thus restraining excitation
and mediating antiepileptic and neuroprotective actions.
[Back to top]
Co-Existence of GABA and Glu Transporters in the Central
Nervous System
Gianni Bonanno, Luca Raiteri, Silvio Paluzzi, Simona Zappettini,
Cesare Usai and Maurizio Raiteri
Co-localization of transporters able to recapture the released
or endogenously synthesized transmitter (homotransporters)
and of transporters that can selectively take up transmitters/modulators
originating from neighbouring structures (heterotransporters)
has been demonstrated to occur within the same axon terminal
of several neuronal phenotypes. Activation of terminal heterotransporters
invariably leads to the release of the transmitter specific
to the terminal. Heterotransporters are also increasingly
reported to exist on neuronal soma/dendrites and nerve terminals,
on the basis of morphological experiments. The functions of
somatodendritic heterotransporters has been investigated only
in a very limited number of cases. Release-regulating GABA
heterotransporters of the GAT-1 type exist on Glu nerve terminals
in different rodent brain regions including spinal cord. Activation
of GABA heterotransporters provokes release of Glu, which
takes place by reversal of the Glu homotransporter and by
anion channel opening. Interestingly, the release of Glu induced
by GABA in spinal cord is dramatically enhanced in a transgenic
mouse model of amyotrophic lateral sclerosis and this effect
seems to represent the most precocious mechanism that increases
extracellular Glu concentration, reported to occur in the
pathomechanism.
[Back to top]
Role for GABA and Glu Plasma Membrane Transporters
in the Interplay of Inhibitory and Excitatory Neurotransmission
László Héja, Kinga Karacs and Julianna
Kardos
Neurotransmitter plasma membrane transporters do have much
more to perform than simply terminating synaptic transmission
and replenishing neurotransmitter pools. Findings in the past
decade have evidenced their function in maintaining physiological
synaptic excitability, and their actions in critical or pathological
conditions, also. Conclusively these findings indicated a
previously unrecognized role for neurotransmitter plasma membrane
transporters in both, synaptic and nonsynaptic signaling.
Major inhibitory and excitatory neurotransmitters within the
brain, GABA and Glu, have long been considered to operate
through independent systems (GABAergic or Gluergic),
each of them characterized by its own localization, function
and dedicated GABAergic or Gluergic cell
phenotypes. Recent advances, however, have challenged this
long-standing paradigm. Localization of GABA in Gluergic
terminals and Glu in GABAergic cells were reported.
Specific plasma membrane transporters for GABA and Glu are
also co-localized in different brain areas. Although, their
role in regulating each other’s signal is still far
from being understood, emerging lines of evidence on interplaying
GABAergic and Gluergic processes through
plasma membrane transporters opens up a new avenue in the
field of more specific therapeutic intervention.
[Back to top]
Editorial
Potassium channels are membrane proteins which selectively
allow potassium ions to flow across the cell membrane, following
the electrochemical gradient. Since the extracellular potassium
concentration is greatly lower than the intracellular one,
the opening of potassium channels typically determines an
outward current of these ions, causing a shift of the resting
membrane potential towards the potassium equilibrium potential
(hyperpolarisation) or the recovery of the resting potential
in a depolarised membrane (repolarisation). Both these mechanisms
can counteract the excitatory (depolarising) stimuli, generally
due to the inward flows of other important cationic species
(calcium and sodium).
This fundamental role of potassium channels is inmost involved
in almost all the main cell activities, such as the excitability
of neurons and muscle cells, the shaping of action potentials,
the coupling of many chemical and or mechanical stimuli with
given intracellular events, the function of secretive cells,
etc., and thus drugs activating potassium channel seem to
represent interesting tools for the potential treatment of
several pathological conditions. Because of their relaxing
effects on smooth muscle cells, they have been investigated
as vasodilators and anti-asthmatic agents. Their neuroprotective
activity furnished a strong rational basis for the use in
neurodegenerative disorders and/or in stroke. Other experimental
studies indicated potassium channel activators as useful agents
for treatment of epilepsy and pain. More recent evidence,
indicating a relevant role of potassium channels expressed
on the myocardial mitochondria in the “ischaemic pre-conditioning”,
suggested an intriguing scenario for potassium channel activators
as innovative cardio-protective anti-ischaemic drugs.
Although all these therapeutic perspectives have been well
supported by a plethora of convincing experimental studies,
the availability of potassium channel activators in the clinical
practice is still quite limited. There are, at least, two
main reasons for this apparent antinomia between the hypothesised
potentialities of these drugs and their real application.
Potassium channels are sub-divided into a very large number
of types and subtypes, but only few of them have been selected
for the development of selective drugs.
Many drugs presently available show an appreciable selectivity
for given potassium channel types, but, generally, these targets
are largely expressed in many districts and, hence, this determines
the presence of several side-effects accompanying a wished
pharmacological activity.
Therefore, the individuation of a given potassium channel
subtype closely associated with a particular role (and, ideally,
in a particular district), as well as the development of appropriate
pharmacophore models able to confer to a potassium channel
activator a satisfactory selectivity for a given sub-type
(or, at least, to confer an adequate tissue-selectivity due
to pharmacokinetic properties), seems to represent the most
challenging issue for the pharmacologists and medicinal chemists
working in the field of potassium channel drugs.
In this special issue, William Dalby-Brown and colleagues
present an intriguing and detailed review focused on the voltage-operated
potassium channel KV7
type as a recent target of the pharmacological/pharmaceutical
investigation. Indeed, some subtypes of this channel play
clear and distinct roles in human diseases, offering some
promising perspectives for the development of selective modulators
(openers as well as blockers).
The large-conductance calcium-activated potassium (BK) channel,
has been the topic of intense research, in the recent years.
A relatively large amount of heterogeneous compounds acts
as BK-openers and many of them have been obtained from the
structural development of pioneer benzimidazolone derivatives.
In his interesting paper, Sheng-Nan Wu and co-workers give
an overview on the pharmacological roles of BK channels and
on the BK-activating properties of several compounds, which
are not structurally related with the benzimidazolone BK-activators
and, therefore, can represent a useful and original template
for the development of new chemical classes of BK-openers.
The ATP-sensitive (KATP)
one is surely the most studied, among the different types
of potassium channels and about two decades of investigations
furnished a wide collection of KATP-activators.
Indeed, these channel modulators belong to extremely diversified
chemical families and the large number of compounds of each
family allowed to trace clear structure-activity relationships.
In his magistral review, Raimund Mannhold reports the various
physiological roles of KATP-channels,
the relative potential therapeutic application of KATP-openers
and the several chemical classes of such drugs, with a detailed
description of the fundamental structure-activity relationships.
Furthermore, in their paper, Violetta Cecchetti and colleagues
present a deep study on the benzopyran-based KATP-activators,
i.e. the widest chemical class of such agents, with particular
emphasis on the main changes carried out on the benzopyran
heterocycle, and with a careful explanation of the most relevant
chemical approaches, useful for the synthesis of such derivatives.
Dr. Vincenzo Calderone
Dipartimento di Psichiatria, Neurobiologia,
Farmacologia e Biotecnologie
Università di Pisa
Via Bonanno, 6
I-56126, Pisa
Italy
[Back to top]
Kv7
Channels: Function, Pharmacology and Channel Modulators
William Dalby-Brown, Henrik H. Hansen, Mads P.G. Korsgaard,
Naheed Mirza and Søren-P Olesen
KV7
channels are unique among K+ channels, since four
out of the five channel subtypes have well-documented roles
in the development of human diseases. They have distinct physiological
functions in the heart and in the nervous system, which can
be ascribed to their voltage-gating properties. The KV7
channels also lend themselves to pharmacological modulation,
and synthetic openers as well as blockers of the channels,
regulating neuronal excitability, have existed even before
the KV7
channels were identified by cloning. In the present review
we give an account on the focused efforts to develop selective
modulators, openers as well as blockers, of the KV7
channel subtypes, which have been undertaken during recent
years, along with a discussion of the KV7
ion channel physiology and therapeutic indications for modulators
of the neuronal KV7
channels.
[Back to top]
Pharmacological Roles of the Large-Conductance
Calcium Activated Potassium Channel
Sheng-Nan Wu, Adonis Z. Wu and Ming-Wei Lin
The gating of large-conductance Ca2+-activated
K+ (BKCa)
channel is primarily controlled by intracellular Ca2+
and/or membrane depolarization. These channels play a role
in the coupling of excitation-contraction and stimulus-secretion.
A variety of structurally distinct compounds may influence
the activity of these channels. Squamocin, an Annonaceous
acetogenin, could interact with the BKCa
channel to increase the amplitude of Ca2+-activated
K+ current in coronary smooth muscle cells. Its
stimulatory effect is related to intracellular Ca2+
concentrations. In inside-out patches, application of ceramide
to the bath suppressed the activity of BKCa
channels recorded from pituitary GH3
cells and from retinal pigment epithelial cells. ICI-182,780,
an estrogen receptor antagonist, was found to modulate BKCa-channel
activity in cultured endothelial cells and smooth muscle cells
in a mechanism unlinked to the inhibition of estrogen receptors.
Caffeic acid phenethyl ester (CAPE) and its analogy, cinnamyl-3,4-dihydroxy-α-cyanocinnamate,
could directly increase the activity of BKCa
channels in GH3
cells. CAPE also reduced the frequency and amplitude of intracellular
Ca2+ oscillations in these cells. The CAPE-stimulated
activity in BKCa
channels is thought to be unassociated with its inhibition
of NF-κB
activation. Cilostazol, an inhibitor of cyclic nucleotide
phosphodiesterase, could stimulate BKCa
channel-activity and reduce the firing of action currents
simultaneously in GH3
cells. Therefore, the regulation by these compounds of BKCa
channels may in part be responsible for their regulatory actions
on cell functions.
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Structure-Activity Relationships of KATP
Channel Openers
Raimund Mannhold
Given their many physiological functions, KATP
channels represent promising drug targets. Sulfonylureas like
glibenclamide block KATP
channels; they are used in the therapy of type 2 diabetes.
Openers of KATP
channels (KCOs) e.g. relax smooth muscle and induce hypotension.
KCOs are chemically heterogeneous and include as different
classes as the benzopyrans, cyanoguanidines, thioformamides,
thiadiazines and pyridyl nitrates. Examples for new chemical
entities more recently developed as KCOs include cyclobutenediones,
dihydropyridine related structures, and tertiary carbinols.
Structure-activity relationships of the main chemical classes
of KCOs are discussed.
[Back to top]
From Cromakalim to Different Structural Classes
of KATP
Channel Openers
Violetta Cecchetti, Oriana Tabarrini and Stefano Sabatini
ATP-Sensitive potassium channel openers (KATPCOs)
are a group of compounds with a broad spectrum of potential
therapeutic applications, as they constitute efficient tools
for dampening cell excitability. Interest in the KATPCOs
was triggered in the early 1980s by the discovery of the benzopyran-based
structure cromakalim (CRK), which is a powerful smooth muscle
relaxant. CRK can be considered the archetype of KATPCOs
and is by far the most mimicked structure. In many structure-activity
studies various substitutions have been made at the different
positions of the benzopyran ring permitting the optimal activity
to be correlated with a specific set of structural characteristics
and stereochemical features of the molecule. Thus, many potent
benzopyran derivatives have been identified. The benzopyran
nucleus itself has also been modified in both the aromatic
ring and in the pyran moiety. The intention of this review
is to bring together all the different structural classes
of KATPCOs
arising from the replacement of CRK benzopyran-based structure
with various ring systems; design, structure-activity relationship,
and synthesis will be given.
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