Mini-Reviews in Medicinal Chemistry, Volume 5, No. 6, 2005
Contents
Allosteric Modulators of G
Protein-Coupled Receptors
Executive Editor: Arthur
Christopoulos
Editorial
Arthur
Christopoulos
Allosterism at Muscarinic Receptors: Ligands
and Mechanisms Pp.523-543
Allosteric Modulation of the Adenosine Family
of Receptors Pp.545-553
Zhan-Guo
Gao, Soo-Kyung Kim, Adriaan P. IJzerman and Kenneth A. Jacobson
Allosteric Modulation of Dopamine Receptors Pp.555-561
John
A. Schetz
General Reviews
A Review on Quantitative Structure-Activity
Relationships (QSARs) of Natural and Synthetic Antioxidants Compounds Pp.563-574
A.C.
Kontogiorgis, A.E. Pontiki and D. Hadjipavlou-Litina
Inhibitors of Membrane Receptors Involved
with Leukocyte Extravasation Pp.575-584
Gerd
Bendas
Structure-Activity Relationships for the
Design of Small-Molecule Inhibitors
Pp.100%-593
Adriano
D. Andricopulo and Carlos A. Montanari
Recent Advances in Neuromuscular Blocking
Agents Pp.595-606
Darius
P. Zlotos
Abstracts
[Back to top] Editorial
Arthur
Christopoulos
Cell-surface G
protein-coupled receptors (GPCRs) constitute nearly 5% of the human genome,
making them the largest superfamily of all receptor proteins. Approximately 300
– 350 of a total of 700 – 1000 GPCRs are the “non-sensory” GPCRs, which
represent the main drug targets for the majority of medicines currently
available. In particular, the “rhodopsin-like” Class I (Family A) GPCRs are
pre-eminent therapeutic targets. Given that half of the non-sensory GPCRs are
“orphan” receptors, it is evident that GPCR-based drug discovery will remain a
vital practice well into the new millennium.
The classic
approach to GPCR-based drug discovery has long been the optimization of lead
molecules to target the “orthosteric” site on the receptor, i.e., the site that
is recognized by the endogenous agonist for that receptor. Orthosteric ligands
have traditionally been classed as agonists, neutral (competitive) antagonists and
inverse agonists. However, it is now becoming recognized that many GPCRs
possess additional, “allosteric”, binding sites that modulate receptor activity
through conformational changes transmitted to the orthosteric site or directly
to effector coupling sites. The structure-activity relationships that govern
orthosteric effects do not apply to allosteric binding sites, leading to a
greater scope for ligand fishing in the chemical space encompassing
biologically active molecules. Furthermore, allosteric modulator ligands of
GPCRs possess a number of advantages over classic orthosteric drugs, including
a greater potential for receptor selectivity and a higher safety in overdose
due to a ceiling level to their effect.
Despite their theoretical
advantages, allosteric interactions are more complex than orthosteric
interactions, and the manifestations of allosterism at GPCRs are many and
varied. Thus, the successful detection, validation and quantification of
allosteric phenomena at GPCRs require modifications of standard approaches used
to screen for orthosteric ligands. The current paucity of allosteric modulators
in the known population of biologically active molecules is likely due to the
fact that classic high-throughput screens are biased towards the detection of
orthosteric ligands, but functional assays have now overtaken
radioligand-binding assays as the high-throughput method of choice, and
allosteric ligands that have minimal effects on orthosteric binding are being
discovered through their effects on receptor signalling. Nevertheless, the
optimal detection of novel allosteric ligands requires the combination of both
standard functional and modulator-optimized binding assays.
This issue of
Mini-Reviews in Medicinal Chemistry contains three reviews from international
leaders in the study of Class I GPCR allosterism. Birdsall and Lazareno provide
an excellent overview on the methodological approaches and pitfalls associated
with the detection and quantification of allosteric modulator ligands, using
the muscarinic acetylcholine receptors as a prototypical example. A
structure-activity focus is provided in the review by Gao, Kim, IJzerman and
Jacobson on allosteric modulators of the adenosine family of receptors.
Finally, Schetz outlines the various modes of modulation of the dopamine family
of GPCRs. These reviews are particularly timely, as there are now a number of
allosteric modulators in clinical trials with many more likely to eventuate
from current drug discovery programs. I am extremely grateful to the
contributors for ensuring that this issue will become a valuable resource to
others in the growing field of GPCR allosterism.
[Back to top] Allosterism at Muscarinic Receptors: Ligands and
Mechanisms
N.J.M.
Birdsall and S. Lazareno
The evaluation of
allosteric ligands at muscarinic receptors is discussed in terms of the ability
of the experimental data to be interpreted by the allosteric ternary complex
model. The compilation of useful SAR information of allosteric ligands is not
simple, especially for muscarinic receptors, where there are multiple
allosteric sites and complex interactions.
[Back to top] Allosteric Modulation of the Adenosine Family
of Receptors
Zhan-Guo
Gao, Soo-Kyung Kim, Adriaan P. IJzerman and Kenneth A. Jacobson
Allosteric
modulators for adenosine receptors (ARs) are of an increasing interest and may
have potential therapeutic advantage over orthosteric ligands. Benzoylthiophene
derivatives (including PD 81,723), 2-aminothiazolium salts, and related
allosteric modulators of the A1 AR have been studied. The
benzoylthiophene derivatives were demonstrated to be selective enhancers for
the A1 AR, with little or no effect on other subtypes of ARs.
Allosteric modulation of the A2A AR has also been reported. A3
allosteric enhancers may be predicted to be useful against ischemic conditions.
We have recently characterized two classes of A3 AR allosteric
modulators: 3-(2-pyridinyl)isoquinolines (e.g. VUF5455) and
1H-imidazo-[4,5-c]quinolin-4-amines (e.g. DU124183), which selectively
decreased the agonist dissociation rate at the human A3AR but not at
A1 and A2A ARs. DU124183 left-shifted the agonist
conc.-response curve for inhibition of forskolin-stimulated cAMP accumulation
in intact cells expressing the human A3AR with up to 30%
potentiation of the maximal efficacy. The increased potency of A3
agonists was evident only in the presence of an A3 antagonist, since
VUF5455 and DU124183 also antagonized, i.e. displaced binding at the
orthosteric site, with Ki values of 1.68 and 0.82 µM, respectively.
A3AR mutagenesis studies implicated F1825.43 and N2747.45
in the action of the enhancers and was interpreted using a rhodopsin-based A3AR
molecular model, suggesting multiple binding modes. Amiloride analogues,
SCH-202676 (N-(2,3-diphenyl-1,2,4-thiadiazol-5(2H)-ylidene)methanamine),
and sodium ions were demonstrated to be common allosteric modulators for at
least three subtypes (A1, A2A, and A3) of ARs.
[Back to top] Allosteric Modulation of Dopamine Receptors
John
A. Schetz
Allosteric
modulators allow for the fine-tuning of receptor responses to endogenous
neurotransmitters and exogenous therapeutic agents. Different types of
allosteric modulation of dopamine receptors are discussed as well as the
significance of such modulation in the control of normal biological processes
and in the treatment of disease.
[Back to top] A Review on Quantitative Structure-Activity
Relationships (QSARs) of Natural and Synthetic Antioxidants Compounds
A.C.
Kontogiorgis, A.E. Pontiki and D. Hadjipavlou-Litina
During the last
decade an increasing number of reports describe the roles of active oxygen species
in the development or exacerbation of various kinds of diseases. Antioxidants
are of great interest because of their involvement in important biological and
industrial processes. They have been found to possess anticancer,
anti-cardiovascular, anti-inflammatory and many other activities.
Many attempts have
been made to elucidate the QSAR of antioxidants by using different
physicochemical parameters. Unfortunately the limited number of antioxidants
and the unavailable s Hammett values of
complex substituents did not lead to significant results in regression
analysis. The redox potentials are well correlated to the antioxidant
activities. In this report we will attempt to collect and discuss all the
published results concerning the QSAR research on natural and synthetic
antioxidants compounds.
[Back to top] Inhibitors of Membrane Receptors Involved
with Leukocyte Extravasation
Gerd
Bendas
The migration of leukocytes
from the blood stream to sites of infection is a key event in cellular immune
response, mediated by multiple types of molecules including several adhesion
receptors. The inhibition of adhesion receptors holds great promise for novel
therapeutical strategies to treat chronic inflammatory disorders or autoimmune
diseases. This review reports on recent advances in adhesion-based therapeutics
and focuses on structural classification of selectin and integrin inhibitors.
[Back to top] Structure-Activity Relationships for the
Design of Small-Molecule Inhibitors
Adriano
D. Andricopulo and Carlos A. Montanari
One of the most
important stages of the drug discovery process is the generation of lead
compounds.Structure-activity relationships (SAR) are well-integrated in modern
drug discovery and have been largely used for the finding of new leads,
scaffold generation, the optimization of receptor or enzyme affinity, as well
as of pharmacokinetic and physicochemical properties. This review highlights
some SAR approaches that can be used to optimize leads through a continuous,
multi-step process based on knowledge gained at each stage, thus exploiting SAR
in the design of selective, potent, small-molecule drug candidates.
[Back to top] Recent Advances in Neuromuscular Blocking
Agents
Darius
P. Zlotos
Since the
introduction of (+)-tubocurarine into anaesthetic and surgical practice (1942),
a number of non-depolarizing neuromuscular blocking agents (NMBs) with improved
pharmacological properties have been developed during the last sixty years.
However, after withdrawal of rapacuronium from clinical use, there is still a
need for an ultra-short acting non-depolarizing muscle relaxant with rapid
onset as substitution for the polarizing suxamethonium, which has several
undesirable side-effects. In this paper, structure-activity relationships
within four different series of NMBs (tetrahydroisoquinolinium, bistropinyl
diester, aminosteroid, and amino peptide analogues) published in this
millennium have been reviewed. The NMB properties of the most promising drug
candidates from each series were discussed and compared to those of the already
existing muscle relaxants.