Current Topics in Medicinal Chemistry, Volume 4, No. 3, 2004
Contents
Central Nicotinic
Receptors and their Ligands: Setting the Scene
Nicotine and Nicotinic Receptor Involvement
in Neuropsychiatric Disorders Pp.267-282
Paul
Newhouse, Abhay Singh and Alexandra Potter
Physiological Roles of Neuronal Nicotinic
Receptors Subtypes: New Insights on the Nicotinic Modulation of
Neurotransmitter Release, Synaptic Transmission and Plasticity Pp. 283-297
E.
Sher, Y. Chen, T.J.W. Sharples, L.M. Broad, G. Benedetti, R. Zwart, G.I.
McPhie, K.H. Pearson, T. Baldwinson and G. De Filippi
Design of Ligands for the Nicotinic
Acetylcholine Receptors: The Quest for Selectivity Pp.299-334
William
H. Bunnelle, Michael J. Dart and Michael R. Schrimpf
Neuronal Nicotinic Acetylcholine Receptor
Agonists: Pharmacophores, Evolutionary QSAR and 3D-QSAR models Pp. 335-360
Orazio
Nicolotti,Cosimo Altomare,Marialuisa Pellegrini-Calace and Angelo Carotti
Receptor Binding Thermodynamics at the
Neuronal Nicotinic Receptor Pp.
361-368
Pier
Andrea Borea, Katia Varani, Stefania Gessi,
Nicotinic Acetylcholine Receptor Agonists: A
Potential New Class of Analgesics Pp.369-384
Michael
W. Decker, Lynne E. Rueter, and R. Scott Bitner
Abstracts
[Back to top] Nicotine and Nicotinic Receptor Involvement
in Neuropsychiatric Disorders
Paul
Newhouse, Abhay Singh and Alexandra Potter
Advances in the understanding of the neurobiology of the
nicotinic receptor have started to be matched by an appreciation of the
potential role of these receptors in a variety of neuropsychiatric disorders.
While alterations in nicotinic receptor number and/or function have been
associated with such conditions as Alzheimer's disease for several years, there
is increasing evidence that nicotinic receptor function may play a significant
role in other disorders as well including schizophrenia, Parkinson's disease,
anxiety disorders, and attention deficit-hyperactivity disorder (ADHD).
Research in our laboratory and those of other investigators have utilized
sophisticated psychopharmacological, cognitive, electrophysiological,
neuroimaging and other techniques to assess the impact of nicotinic receptor
modulation on the clinical expression of these disorders. This manuscript
reviews data, both experimental and clinical, relating to the role of nicotine
and/or nicotinic receptor function in a variety of neuropsychiatric disorders
with the perspective of developing appropriate targets for therapeutic drug
development.
[Back to top] Physiological Roles of Neuronal Nicotinic
Receptors Subtypes: New Insights on the Nicotinic Modulation of
Neurotransmitter Release, Synaptic Transmission and Plasticity
E.
Sher, Y. Chen, T.J.W. Sharples, L.M. Broad, G. Benedetti, R. Zwart, G.I.
McPhie, K.H. Pearson, T. Baldwinson and G. De Filippi
Nicotinic acetylcholine receptors (nAChRs) are widely
expressed in the mammalian central nervous system (CNS). Despite this, very
little was known, until recently, about their physiological role. In the
periphery, nicotinic receptors mediate vital excitatory fast synaptic
cholinergic transmission at both the neuromuscular junction and ganglia. In the
brain, this role has been mainly “delegated” to glutamate receptors.
The very broad cholinergic innervations of most brain areas,
including the cortex, have implicated this system, and brain nicotinic
receptors in particular, in a unique “modulatory” role of other transmitters
systems.
Recent evidence confirms, on one hand, that brain nicotinic
receptors have a dominant “presynaptic” modulatory function, controlling the
release of both acetylcholine (auto-receptors) and other neurotransmitters (hetero-receptors).
On the other hand, more experimental data support the idea that a variable
component of fast synaptic transmission in the brain can also be mediated by
“postynaptic” nicotinic receptors, which, in turn, can control cell
excitability.
A challenging goal is to identify which one of the plethora
of nicotinic receptor subtypes is mediating each effect in
different brain areas, and which of these receptors and
functions are lost or affected in different human neuro-psychiatric isorders.
Needless to say, a better understanding of the physiological
role of brain nicotinic receptors will drive our quest for more
selective and efficacious nicotinic receptor targeted
therapeutic agents.
[Back to top] Design of Ligands for the Nicotinic
Acetylcholine Receptors: The Quest for Selectivity
William
H. Bunnelle, Michael J. Dart and Michael R. Schrimpf
In the last decade, nicotinic acetylcholine receptors
(nAChRs) have emerged as important targets for drug discovery. The therapeutic
potential of nicotinic agonists depends substantially on the ability to
selectively activate certain receptor subtypes that mediate beneficial effects.
The design of such compounds has proceeded in spite of a general shortage of
data pertaining to subtype selectivity. Medicinal chemistry efforts have been
guided principally by binding affinities to the a4b2
and/or a7
subtypes, even though these are not predictive of agonist activity at either
subtype. Nevertheless, a diverse family of nAChR ligands has been developed,
and several analogs with promising therapeutic potential have now advanced to
human clinical trials. This paper provides an overview of the
structure-affinity relationships that continue to drive development of new
nAChR ligands.
[Back to top] Neuronal Nicotinic Acetylcholine Receptor
Agonists: Pharmacophores, Evolutionary QSAR and 3D-QSAR models
Orazio
Nicolotti,Cosimo Altomare,Marialuisa Pellegrini-Calace and Angelo Carotti
Neuronal nicotinic acetylcholine ion channel receptors (nAChRs)
exist as several subtypes and are involved in a variety of functions and
disorders of the central nervous system (CNS), such as Alzheimer’s and
Parkinson’s diseases. The lack of reliable information on the 3D structure of
nAChRs prompted us to focus efforts on pharmacophore and structure-affinity
relationships (SAFIRs). The use of DISCO (DIStance COmparison) and
Catalyst/HipHop led to the formulation of a pharmacophore that is made of three
geometrically unrelated features: (i) an ammonium head involved in coulombic
and/or H-bond interactions, (ii) a lone pair of a pyridine nitrogen or a
carbonyl oxygen, as H-bond acceptor site, and (iii) a hydrophobic molecular
region generally constituted by aliphatic cycles. The quantitative SAFIR
(QSAFIR) study was carried out on about three hundred nicotinoid agonists, and
coherent results were obtained from classical Hansch-type approach, 3D QSAFIRs,
based on Comparative Molecular Field Analysis (CoMFA), and trade-off models
generated by Multi-objective Genetic QSAR (MoQSAR), a novel evolutionary
software that makes use of Genetic Programming (GP) and multi-objective
optimization (MO). Within each congeneric series, Hansch-type equations
revealed detrimental steric effects as the major factors modulating the receptor
affinity, whereas CoMFA allowed us to merge progressively single-class models
in a more global one, whose robustness was supported by crossvalidation, high
prediction statistics and satisfactory predictions of the affinity data of a
true external ligand set (r2 pred = 0.796). Next, MoQSAR
was used to analyze a data set of 58 highly active nicotinoids characterized by
56 descriptors, that are log P, MR and 54 low inter-correlated WHIM (Weighted
Holistic Invariant Molecular) indices. Equivalent QSAFIR models, that represent
different compromises between structural model complexity, fitting and internal
model complexity, were found. Our attention was mostly engaged by a number of
nonlinear QSAFIRs, which relate nAChR affinity with the log P and directional
WHIM descriptors. The results reviewed herein show as QSAFIRs may helpfully
complement the pharmacophores, thus enhancing the applicability of
computer-aided methodologies in the field of nAChR agonists.
[Back to top] Receptor Binding Thermodynamics at the
Neuronal Nicotinic Receptor
Pier
Andrea Borea, Katia Varani, Stefania Gessi,
Simple determination of KA or KD
values makes it possible to calculate the standard free energy DG°
= - RTlnKA = RT lnKD (T= 298.15 K) of the binding
equilibrium but not that of its two components as defined by the Gibbs equation
DG°
= DH°
- TDS°
where DH°
and DS°
are the equilibrium standard enthalpy and entropy, respectively. Recently, it
has been shown that the relative DH° and DS° magnitudes can
often give a simple “in vitro” way for discriminating “the effect”, that is the
manner in which the drug interferes with the signal transduction pathways. This
particular effect, called “thermodynamic discrimination”, results from the fact
that binding of antagonists may be enthalpy-driven and that of agonists
entropy-driven, or vice-versa. In the past, the thermodynamic discrimination
was reported for the b-adrenergic G-protein-coupled receptor
(GPCR) and confirmed later for adenosine A1, A2A and A3
receptors. Moreover, it has been found that the binding of all ligand-gated
ion-channel receptors (LGICR) investigated was thermodynamically discriminated.
In particular, affinity constants for typical neuronal nicotinic receptor
ligands were obtained by both saturation and inhibition experiments with the
radioligand [3H]-cytisine, a ganglionic nicotinic agonist.
Thermodynamic parameters indicated that agonistic binding was both enthalpy-
and entropy-driven, while antagonistic binding was totally entropy-driven.
These results have shown that neuronal nicotinic receptor agonists and
antagonists were thermodynamically discriminated. On these grounds, the
thermodynamic behaviour makes it possible to discriminate drug pharmacological
profiles in vivo through binding experiments in vitro.
[Back to top] Nicotinic Acetylcholine Receptor Agonists: A
Potential New Class of Analgesics
Michael
W. Decker, Lynne E. Rueter, and R. Scott Bitner
Current analgesics, such as opioids and nonsteroidal
anti-inflammatory drugs (NSAIDs), are largely refinements of approaches
available for more than 100 years and have critical liabilities and
limitations. A number of new molecular targets for analgesia have been proposed
in recent years, including the neuronal nicotinic acetylcholine receptor
(nAChR). Agonists at neuronal nAChRs have antinociceptive effects in a variety
of preclinical pain models. Moreover, nicotine can decrease
experimentally-induced pain in humans without disrupting normal tactile
sensation. These data from both experimental animals and humans suggest that
compounds targeting neuronal nAChRs may represent a new class of analgesic
agents. In this paper, we provide brief overviews of the physiology of pain, the
animal models used to assess potential analgesics preclinically, and the
biology of nAChRs. We then provide a review of preclinical data on the
antinociceptive effects of a variety of neuronal nAChR agonists and a
discussion of potential mechanisms, including evidence that antinociception is
mediated by activation of brainstem nuclei with descending inhibitory inputs to
the spinal cord. An evaluation of the clinical potential of this approach must
also consider potential side effects. Undesirable side effects of nicotine are
well known, but as we will discuss in detail, these effects are not produced by
all neuronal nAChR agonists and the existence of neuronal nAChR subtypes may
provide a basis for separating therapeutic effects from toxicities.