Jeffrey Conn talks with
ScienceWatch.com and answers a few questions about
this month's New Hot Paper in the field of Pharmacology
&Toxicology.
Article Title: Allosteric modulators of GPCRs: a novel approach
for the treatment of CNS disorders
Authors: Conn, PJ;Christopoulos, A;Lindsley,
CW
Journal: NAT REV DRUG DISCOV, Volume: 8, Issue: 1, Page: 41-54,
Year: JAN 2009
* Vanderbilt Univ Sch Med, Vanderbilt Program Drug Discovery,
Dept Pharmacol, 1215 Light Hall, Nashville, TN 37232 USA.
* Vanderbilt Univ Sch Med, Vanderbilt Program Drug Discovery,
Dept Pharmacol, Nashville, TN 37232 USA.
* Monash Univ, Drug Discovery Biol Lab, Monash Inst Pharmaceut
Sci, Melbourne, Vic 3004, Australia. (addresses have been
truncated.)
Why do you think your paper is highly
cited?
G-protein-coupled receptors (GPCRs) have been among the most successful of
drug targets and are involved, in a fundamental way, in regulating
virtually every cellular or organ system. However, there has been an
impasse for many years in the discovery and development of highly selective
small molecule ligands for several GPCR subtypes.
In recent years, there has been a fundamental advance in developing highly
selective activators and inhibitors of many previously intractable GPCR
subtypes by discovery of allosteric modulators that target sites other than
the normal neurotransmitter or hormone binding site.
In addition to providing high selectivity, these compounds provide multiple
modes of efficacy that can provide much more subtle control of GPCR
function. This is having a major impact on multiple research areas, both by
providing new tools and a new approach to developing therapeutic agents.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
It summarizes studies that are leading to a fundamental shift in our
thinking and provides a synthesis of knowledge that has been developing
over the last five to seven years.
Would you summarize the significance of your paper
in layman's terms?
Jeffrey Conn Research Group at Vanderbilt.
Many marketed drugs act on a class of drug targets that serve as specific
receptors for neurotransmitters. These traditional drugs act as on/off
switches to either activate or inhibit the activity of the receptor.
However, this "all-or-nothing" action can often lead to unwanted side
effects. Also, it has been difficult to develop drugs that only act on one
receptor and not on others.
Discovery of novel drug-like molecules, termed allosteric modulators,
provide a new approach to developing drugs that act as "dimmer switches,"
to have more subtle effects that either increase or decrease the activity
of specific neurotransmitter receptors, and thereby, fine-tune their
activity in such a manner may offer better efficacy, without the same side
effects.
Also, these new molecules have been much more selective for individual
receptor subtypes than have many drugs developed using traditional
approaches.
How did you become involved in this research, and
were there any problems along the way?
I had spent many years trying to develop highly selective agents that act
on individual GPCR subtypes. Highly selective agents for the receptors we
study proved to be impossible to develop. This prevented us from
establishing the physiological roles of these receptors and made them
intractable as drug targets.
We began to reason that the lack of ability to develop highly selective
compounds was likely due to the high level of conservation of the
neurotransmitter binding site across receptor subtypes.
Based on this, we reasoned that we may be able to develop more selective
compounds by moving away from the normal neurotransmitter binding site and
developing allosteric modulators.
This approach was highly successful, and we and other groups have now
developed highly selective allosteric modulators for multiple GPCR
subtypes. This paper is a review of studies by multiple scientists in this
field.
Where do you see your research leading in the
future?
This research is leading to fundamental advances in multiple areas,
including our understanding of the mechanisms of GPCR signaling, mechanisms
involved in regulation of multiple cell and biological systems, and novel
approaches to treatment of human disease.
There are now two allosteric modulators that are marketed for treatment of
human disorders.
These are cinacalcet (Sensipar®; Amgen). This is a positive
allosteric modulator (PAM) of the calcium-sensing receptor (CasR), which
increases sensitivity to circulating calcium. CasR is involved in the
regulation of calcium homeostasis and renal calcium resorption and
cinacalcet is used for treatment of hyperparathyroidism.
More recently, maraviroc (Celsentri®; Pfizer), a negative
allosteric modulator (NAM) of the chemokine receptor CCR5, was launched for
the treatment of HIv infections. Maraviroc binds to CCR5, stabilizing a
receptor conformation that has lower affinity for the HIV virus, thereby
blocking CCR5-dependent entry of HIV-1 into cells.
There are multiple metabotropic glutamate receptor 5 (mGluR5) NAMs in
clinical development but none are on the market. In the future, this is
likely to develop even further for multiple disorders.
Also, we are now establishing compounds which selectively modulate coupling
of receptors to some, but not all, signaling pathways. This is likely to be
a major focus of future studies. It will provide information about specific
signaling systems involved in regulating different physiological responses
and more specific targeting of individual signaling pathways for the
development of therapeutic agents.
P. Jeffrey Conn, Ph.D.
Lee E. Limbird Professor of Pharmacology
Director, Vanderbilt Program in Drug Discovery
Department of Pharmacology
Vanderbilt University Medical Center
Nashville , TN, USA Web
Why do you think your paper is highly
cited?
