Chemical Synthesis and Biological Evaluation of 18-Methoxycoronaridine (18-MC) as a Potential Anti-addictive Agent Pp113-123
Aptamers as Tools to Study Dysfunction in the Neuronal
System Pp 125-132
Henning Ulrich and Armanda M. Gameiro
Opioid
Peptides and Their Glycoconjugates: Structure-Activity Relationships Pp 133-154
S. Horvat
Acetylcholinesterase: Mechanism of Catalysis and Inhibition Pp 155-170
V. Tõugu
Clinical Pharmacology of Serotonin Receptor Type 3 (5-HT3) Antagonists Pp 171-199
Zafar H. Israili
[Back to top] Chemical Synthesis and Biological Evaluation of 18-Methoxycoronaridine (18-MC) as a Potential Anti-addictive Agent
Ibogaine (1a), one of the psychoactive indole alkaloids found in the root bark of the West African shrub, Tabernanthe iboga, has purported efficacy in treating multiple forms of drug abuse. A single oral treatment with ibogaine or its salts, in the doses of 6 to 19 mg/kg, or a series of four treatments may, respectively, eliminate addictive behavior for up to 6 months or three years.
In rats, ibogaine (40 mg/kg) decreases intravenous self-administration of both morphine and cocaine and oral self-administration of ethanol and nicotine. However, ibogaine also exerts several serious side effects including tremors, toxic degeneration of Purkinje cells in the brain and an acute depressant effect on responding for water in rats. Such side effects may restrict the use of ibogaine to treat human addictive disorders. These problems led us to develop novel synthetic ibogaine congeners that mimic ibogaine’s therapeutic profile, but without side effects. 18-Methoxycoronaridine (18-MC, 2c), a novel iboga alkaloid congener, has been synthesized and evaluated as a potential anti-addictive agent. Racemic 18-MC has been synthesized in 13 steps, with overall 7% yield. Both enantiomers of 18-MC have been obtained, either by chemical resolution of (±)-18-MC or by enantioselective total synthesis using chiral auxiliaries. Like ibogaine, 18-MC decreases the intravenous self-administration of morphine and cocaine and the oral self-administration of ethanol and nicotine in rats. However, 18-MC does not evidence ibogaine’s side effects. Thus, 18-MC has potential as a safe and effective treatment for multiple forms of drug abuse.
[Back to top] Aptamers as Tools to Study Dysfunction in the Neuronal System
Combinatorial library approaches combining organic synthesis and molecular biology have made promising developments in the discovery of new ligands and antagonists binding to proteins that participate in dysfunction and disease. The peptide and oligonucleotide sequences, referred to as aptamers (latin= to fit) are evolved from random libraries and bind proteins such as neurotransmitter receptors and a transporter with high affinity and specificity and mimic the tertiary structure of natural agonists or antagonists. Several investigations revealed that the transduction of signals by neurotransmitter receptors, regulated by an equilibrium between open and closed channels is disturbed during dysfunction caused by drug abuse and disease. Mechanism-based strategies and future perspectives for the discovery of compounds using peptide and oligonucleotide aptamers that protect normal protein function are discussed.
[Back
to top] Opioid Peptides and Their Glycoconjugates:
Structure-Activity Relationships
Since the discovery of the opioid receptors and their
endogenous ligands, it has been widely recognized that endogenous opioid
peptides produce a large spectrum of central and peripheral effects which
include spinal and supraspinal analgesia, dependence, effects on
gastrointestinal, renal and hepatic functions, cardiovascular and immunological
responses, respiratory depression, and are also involved in neurological
disorders. The intention of this review is to identify and highlight the acomplishments
to date in the design of receptor-selective opioid peptide analogues as well as
of their glycoconjugates which led to the potent ligands most useful as
pharmacological tools or have potential for therapeutic applications. In the
first part of the article, following a brief description of opioid receptors,
and characteristics of m, d and k types, endogenous peptide ligands and their
physiological roles are presented. The chapter concludes with presentation of
the bioactivity profiles of peptide analogues with agonist properties and with
high selectivity for distinct opioid receptor types. In the second part,
synthetic efforts aimed at developing opioid peptide glycoconjugates and the
progress made in this area are reviewed. Impact of the incorporated
carbohydrate moiety on the receptor selectivity, conformation, stability and
bioavailability of the parent peptides is discussed.
[Back to
top] Acetylcholinesterase: Mechanism of Catalysis and Inhibition
V. Tõugu
Recent advances in
the study of the catalytic properties of acetylcholinesterases have been
reviewed. The main biological function of this enzyme is the fast termination
of impulse transmission at cholinegric synapses by rapid hydrolysis of the
neurotransmitter acetylcholine. Acetylcholinesterase has been often
characterized as a perfect enzyme because its catalytic properties have been
tuned to the highest possible limit. However, it seems paradoxical that the
active site of this enzyme is buried deeply inside the enzyme molecule in the
bottom of a narrow gorge restricting the traffic of substrates and products.
The analysis of recent advances in enzymology and data on cholinesterase
revealed rationality of this organization. The primary task of an enzyme
catalyst is to lower the activation barrier for the chemical transformation of
the substrate, and the catalytic power of the enzyme originates in polar
solvation of the transition state by properly oriented dipoles inside the enzyme
molecule. The active site gorge of acetylcholinesterase, containing multiple
potential substrate binding areas, is responsible for “trapping” and delivery
of substrate molecules to the active site. The phenomena of “allosteric
modulation” and substrate inhibition arise as secondary effects of the presence
of the narrow gorge lined with hydrophobic residues.
[Back to top] Clinical Pharmacology of Serotonin Receptor Type 3 (5-HT3) Antagonists
Zafar H. Israili
Serotonin (5-HT), a
neurotransmitter and a neuromodulator, plays an important role in physiological
functions and in many pathological conditions. The actions of 5-HT are mediated
by a variety of 5-HT receptors, which are distributed extensively in the
central nervous system and certain peripheral tissues. A class of drugs which
specifically antagonizes the 5-HT type 3 receptor (5-HT3) now occupy an
important place in the therapy of cancer, since these drugs allow the use of
high-dose cytotoxic treatment by blocking the nausea and vomiting triggered by
cancer chemotherapeutic agents and/or radiotherapy. They are also useful as
prophylactic agents in preventing postoperative nausea and vomiting due to the
anesthetics used in surgical procedures. The 5-HT3 receptor antagonists (with
or without other antiemetic drugs) have become the agents of choice in
controlling emesis because of higher efficacy and relatively lower adverse
effect profile as compared to the conventional antiemetic agents. The major
site of action of these drugs appears to be the central 5-HT3 receptors,
although inhibition of peripheral receptors may also play a role in the control
of vomiting. The clinical efficacy as antiemetic agents and the safety profile
of the various agents in this class is similar. These drugs may also be useful
in the treatment of pain, pruritus, fibromyalgia, gastrointestinal symptoms,
anxiety disorders and alcohol dependency, but not enough clinical data are
available to confirm their role in these disorders. The individual 5-HT3 receptor
antagonists differ in pharmacokinetic properties and potential for drug-drug
interaction.