Current Medicinal Chemistry - Central Nervous System Agents - Volume 1, Issue 2, 2001

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 yearsIn 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 ibogaines 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 7percent yield. Both enantiomers of 18-MC have been obtained, either by chemical resolution of (plus minus)-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 ibogaines side effects. Thus, 18-MC has potential as a safe and effective treatment for multiple forms of drug abuse.

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.

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.

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.

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.