Current Topics in Medicinal Chemistry, Volume 4, No. 1, 2004
Contents
Opioids:
Receptors, Analogs, Biological Functions and Therapeutic Applications
Opioid Receptors and their Ligands Pp.1-17
Anna
Janecka, Jakub Fichna and Tomasz Janecki
New Trends in the Development of Opioid
Peptide Analogues as Advanced Remedies for Pain Relief Pp.19-38
Luca
Gentilucci
Endogenous Opioids and Addiction to Alcohol
and other Drugs of Abuse Pp.39-50
Christina
Gianoulakis
Expression of Opioid Receptors During
Peripheral Inflammation Pp.51-61
Olga
Pol and Margarita M. Puig
Neuropeptides and Gastric Mucosal Homeostasis
Pp.63-73
Gyires,
K.
Substance P: Structure, Function, and
Therapeutics Pp.75-103
Prasanna
Datar, Sudha Srivastava, Evans Coutinho and Girjesh Govil
Recent Advances in the Investigation of the
Bioactive Conformation of Peptides Active at the µ-opioid Receptor.
Conformational Analysis of Endomorphins Pp.105-121
Luca
Gentilucci and Alessandra Tolomelli
Use of NMR and Fluorescence Spectroscopy as
well as Theoretical Conformational Analysis in Conformation -activity Studies
of Cyclic Enkephalin Analogues Pp.123-133
Joanna
Malicka, Cezary Czaplewski, Malgorzata Groth, Wieslaw Wiczk, Stanislaw Oldziej,
Leszek Lankiewicz, Jerzy Ciarkowski, Adam Liwo
Conformational Analysis of Opioid Peptides in
the Solid States and the Membrane Environments by NMR Spectroscopy Pp.135-145
Akira
Naito and Katsuyuki Nishimura
Antagonism in Opioid Peptides: the Role of
Conformation Pp.147-157
Severo
Salvadori and Piero A. Temussi
Abstracts
[Back to top] Opioid Receptors and their Ligands
Anna
Janecka, Jakub Fichna and Tomasz Janecki
This review gives a historical perspective, summarizing
approximately 25 years of research on opioids. The “typical” opioid peptides
produced in the brain, “atypical” opioids encrypted in milk protein or
hemoglobin sequences, and extremely potent and selective opioidsof amphibian
origin are described. The main focus is on the structure-activity relationship
studies of peptide ligands for three main opioid receptor types (m, d, k),
their selectivities and pharmacological activities in
vitro. Chemical modifications that led to obtaining potent and
selective agonists and antagonists for these receptors are discussed.
[Back to top] New Trends in the Development of Opioid
Peptide Analogues as Advanced Remedies for Pain Relief
Luca
Gentilucci
The search for new peptides to be used as analgesics in
place of morphine has been mainly directed to develop peptide analogues or
peptidomimetics having higher biological stability and receptor selectivity.
Indeed, most of the alkaloid opioid counterindications are due to the scarce
stability and the contemporary activation of different receptor types. However,
the development of several extremely stable and selective peptide ligands for
the different opioid eceptors, and the recent discovery of the m-receptor
selective endomorphins, rendered this search less fundamental. In recent years,
other opioid peptide properties have been investigated in the search for new
pharmacological tools. The utility of a drug depends on its ability to
reacappropriate receptors at the target tissue and to remain metabolically
stable in order to produce the desired effect. This review deals with the
recent investigations on peptide bioavailability, in particular barrier
penetration and resistance against enzymatic degradation; with the development
of peptides having activity at different receptors; with chimeric peptides,
with propeptides, and with non-conventional peptides, lacking basic
pharmacophoric features.
[Back to top] Endogenous Opioids and Addiction to Alcohol
and other Drugs of Abuse
Christina
Gianoulakis
There is significant experimental evidence implicating the
endogenous opioid system (opioid peptides and opioid receptors) with the
processes of reward and reinforcement. Indeed, many behaviors associated with
reward and reinforcement, for example feeding behavior, are controlled by
distinct components of the endogenous opioid system located in relevant brain
regions. It has also been shown that regardless of their initial site of action
many drugs of abuse, such as morphine, nicotine, cocaine, alcohol and
amphetamines, induce an increase in the extracellular concentration of dopamine
in the nucleus accumbens. This increased secretion of dopamine in the nucleus
accumbens seems to be a common effect of many drugs of abuse, and it was
proposed that may mediate their rewarding and reinforcing properties.
Furthermore, activation of m opioid receptors in the ventral
tegmental area, or of m and d opioid receptors in
the nucleus accumbens enhances the extracellular concentration of dopamine in
the nucleus accumbens. Thus, stimulation of the activity of distinct components
of the endogenous opioid system either by opioid or by other drugs of abuse,
may mediate some of their reinforcing effects. In this review article, a brief
description of the endogenous opioid system and its implication in the
processes of reward and reinforcement of opioid and other drugs of abuse will
be presented. Furthermore, the use of opioid antagonists in the treatment of
drug addiction will be discussed. Special emphasis will be given to ethanol
addiction, the drug mainly studied in my laboratory.
[Back to top] Expression of Opioid Receptors During Peripheral Inflammation
Olga
Pol and Margarita M. Puig
Opioid receptors (OR) and their mRNA are present in the
central and peripheral nervous system of mammals. In this review we examine the
behavioral effects of opioids and the expression of their receptors during
peripheral inflammation in two experimental models: the rat paw and the mouse
intestine. Inflammation increased the antinociceptive (paw ) and the inhibitory
effects of opioids in the gut (transit, permeability and plasma extravasation)
by inte ra ction with OR loca ted a t peripheral sites. Based on agonist
efficacy, m
> d
>> k-OR
mediate the antinociceptive and antitransit effects of opioids during
inflammation. Intestinal permeability is modulate d by d =
m
>> k-O
R, while k
> d
>>
m-O
R are involved in the inhibition of plasma extravasation. Intestinal
inflammation increased the transcription of m and d-OR
(but not k)
genes in the gut, thus explaining the enhanced antitransit and antisecretory
effects of m
and d-OR
agonists; however, the increased inhibitory effects of k-OR
agonists on plasma extravasation could result from post-transcriptional
regulation of the receptor. Similarly, the increased expression of peripheral m-OR
observed in the rat paw during inflammation, occurs at post-transcriptional
levels and is related to an increased axonal transport from the dorsal root
ganglia to peripheral terminals. The sites and mechanisms implicated in the
increased transcription of m and d-OR during intestinal
inflammation are under investigation.
[Back to top] Neuropeptides and Gastric Mucosal Homeostasis
Gyires,
K.
The role of central nervous system (CNS) in regulation of
gastric function has long been known. The dorsal vagal complex (DVC) has an important
role in regulation of gastric mucosal integrity; it is involved both in mucosal
protection and in ulcer formation. Neuropeptides have been identified in DVC,
the origin of these peptides are both intrinsic and extrinsic. Neuropeptides
are localized also in the periphery, in afferent neurons. The afferent neurons
also have efferent-like function in the gastroinetestinal tract, and
neuropeptides released from the peripheral nerve endings of primary afferent
neurons can induce gastric mucosal protection. Centrally and /or peripherally
injected neuropeptides, such as amylin, adrenomedullin, bombesin,
cholecystokinin, neurotensin, opioid peptides, thyreotropin releasing hormone
and vasoactive intestinal peptide, influence both the acid secretion and the
gastric mucosal lesions induced by different ulcerogens. The centrally induced
gastroprotective effect of neuropeptides may be partly due to a vagal dependent
increase of gastric mucosal resistance to injury; activation of vagal
cholinergic pathway is resulted in stimulation of the release of mucosal prostaglandin and nitric oxide. Furthermore,
release of sensory neuropeptides (calcitonin gene-relatedpeptide, tachykinins)
from capsaicin sensitive afferent fibers are also involved in the centrally
induced gastroprotective effect of neuropeptides.
[Back to top] Substance P: Structure, Function, and
Therapeutics
Prasanna
Datar, Sudha Srivastava, Evans Coutinho and Girjesh Govil
Extensive efforts since 1931, on the structural
determination of the mammalian tachykinin SP by NMR, CD and IR have turned out
to be inconclusive. Studies are now being concentrated on the structural
properties and characteristics of various NK receptors (NK1, NK2
and NK3) with the help of genetics, cloning, receptor engineering,
mutagenesis and modeling. This knowledge is now being fruitfully used in the
development of non-peptide NK1 receptor antagonists that essentially
block the pharmacological effects of SP. It is now being realized that the
simultaneous blockade of two or more receptors gives promising results in
emesis, depression and pulmonary obstructive diseases. In addition to the
synthetic compounds, the discovery of antagonists from natural origin has added
a great value to this field. In this review we have made an attempt to present
the structural characteristicsof SP, its analogs and antagonists, the
structural characteristics of the NK receptor, and structure activity
relationships that have helped to improve the therapeutic utilities of SP
antagonists.
[Back to top] Recent Advances in the Investigation of the
Bioactive Conformation of Peptides Active at the m-opioid Receptor. Conformational Analysis of
Endomorphins
Luca
Gentilucci and Alessandra Tolomelli
Despite of the recent advances in the structural
investigation of complex molecules, the comprehension of the 3D features
responsible for the interaction between opioid peptides and m-
opioid receptors still remains an elusive task. This has to be attributed to
the intrinsic nature of opioid peptides, which can assume a number of different
conformations of similar energy, and to the flexibility of the receptorial
cavity, which can modify its inner shape to host different ligands. Due to this
inherent mobility of the ligand-receptor system, massive efforts devoted to the
definition of a rigid bioactive conformation to be used as a template for the
design of new pharmacologically active compounds might be overstressed. The
future goal might be the design of peptide or nonpeptide ligands capable of
maximizing specific hydrophobic interactions. This review covers the recent
opinions emerged on the nature of the ligand-receptor interaction, and the
development of suitable models for the determination of the bioactive
conformation of peptide ligands active towards m-opioid receptors.
[Back to top] Use of NMR and Fluorescence Spectroscopy as
well as Theoretical Conformational Analysis in Conformation activity Studies of
Cyclic Enkephalin Analogues
Joanna
Malicka, Cezary Czaplewski, Malgorzata Groth, Wieslaw Wiczk, Stanislaw Oldziej,
Leszek Lankiewicz, Jerzy Ciarkowski, Adam Liwo
In this review the conformational studies of natural
enkephalins (H-Tyr-Gly-Gly-Phe- Met-OH; the [Met5]enkephalin and
H-Tyr-Gly-Gly-Phe-Leu-OH; the [Leu5]enkephalin), their acyclic and
cyclic analogues, including those carried out in our laboratory, performed by
experimental and theoretical methods and their combination, are described.
Emphasis is given on the role of conformational constraints introduced by
cyclization on activity at the m and d opioid receptors.
Comparison of the conformations of cyclic enkephalin analogues with high d-receptor
activity with those of potent rigid non-peptide d-receptor agonists
indicates that the proximity of the aromatic side chains in positions 1 and 4
as well as the N-terminal amino group is desirable for the activity at the d
opioid receptors; early conformational studies also suggested that spatial
separation of the aromatic side chains and rigidity of the cyclic backbone is
desirable for m-receptor
activity. The results of our recent conformational studies performed with the
use of fluorescence and NMR spectroscopy as well as theoretical calculations
indicate, however, that these structural features are not necessary for
activity at the m opioid receptors. Methods applied to
the determination of the conformation of flexible peptides, such as Nuclear
Magnetic Resonance (NMR), fluorescence spectroscopy, and theoretical conformational
analysis are also discussed briefly.
[Back to top] Conformational Analysis of Opioid Peptides in
the Solid States and the Membrane Environments by NMR Spectroscopy
Akira Naito and Katsuyuki Nishimura
Determination of conformations and structures of opioid peptides in the membrane environments is an essential step to understand the action of the peptide to the specialized receptors. This information not only gains insight into the structure-function relationship of opioid peptide but also gives proper guidelines to design a new drug to have same neuroendocrine functions. This review provides the structural studies of three types of opioid peptide families such as enkephalin, b-endorphin and dynorphin in the solid states and the membrane environments. The structures of enkephalins show that they take b-bend, extended and double b-bend structures in the crystals. Moreover, enkephalin molecules take a variety of structures in the crystals and are easily converted to the other structures with slightly different torsion angles. On the other hand, b-bend structures are mostly seen in the membrane environments. Membrane bound structure of dynorphin shows that the N-terminus forms a-helixal structure and is inserted into the membrane with the helical axis almost perpendicular to the membrane surface. It is discussed that the helical region of the extracellular loop II of the κ- opioid receptor may interact with the helical region of dynorphin with a high affinity in the membrane environments. b- endorphin takes a-helical structure at N-terminus and the central regions and the rest of regions take unordered structure when they bind to the membrane. Since the membrane bound structures of opioid peptides differ from those of the solution states, membrane association is an important process for exerting the affinity and the selectivity to the specific opioid receptors.
[Back to top] Antagonism in Opioid Peptides: the Role of
Conformation
Severo Salvadori and Piero A. Temussi
The availability of new, highly selective antagonists, in the field of opioid peptides and of other pain peptides, is important both for a better understanding of the interaction of the receptors with their ligands and for their practical relevance.
The design of antagonists is not obvious even when the essential features of agonists are well known. In this review we have examined the main aspects of the problem using, as leading criteria two theoretical models of antagonism and the subdivision of opioid peptides into two functional domains.
The main causes of antagonism have been integrated in two very general models: one, referred to as the participation model, attributes antagonism to the lack, with respect to the parent agonist, of an essential group, whereas another model, attributes antagonism to the misfit of the molecule inside the receptor.
The second criterion is the division of the structure of peptide hormones, originally put forward by Robert Schwyzer, in two functional domains, the message domain, which is responsible of the larger part of the binding affinity of opioid agonists, and an address domain, which dictates most of the peptide specificity.
The most significant achievements
in the design of opioid antagonists are classified according to the relative
importance of chemical constitution, conformation and chirality.