Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 6, Issue 1, 2006

Almost 200 years ago, Serturner isolated morphine and discovered it to be the active ingredient in opium. That was the beginning of modern era research into opiate ligands. There have been several important landmarks over the years in the opiates field, including the discovery and cloning of opioid receptors (such as m, Δ and κ receptors), the discovery of their endogenous opioids (such as the enkephalins, endorphins and dynorphins) and understanding of the cascade of events that produce these peptides from their corresponding proteinaceous precursors. Among the various opioid agonists, selective m-opioid agonists display the best antinociceptive activity but also the highest abuse liability, the Δ agonists have less analgesic activity and the κ agonists have strong central dysphoric effects and may only be used as peripheral analgesics. There is, therefore, a continuous effort on the part of both academia and pharmaceutical companies to develop new synthetic opiate pain relievers having better m-receptor selectivity and fewer side effects. Two endogenous m-receptor ligands have been discovered in recent years: endomorphins 1 and 2. They exhibit a high affinity for the m-opioid receptor and extremely high specificity for the μ in preference to the Δ and κ receptors. In an original approach, nonpeptidic agents were developed based on the secondary structure of the enkephalins and were found to share similarities with the threedimensional structure and receptor selectivity profile of the endomorphins. Other approaches involved modification of known morphine analogs or of endogenous ligands. This review focuses on selective μ ligands discovered or developed in the last decade. The behavioral activity and the medicinal potential of these compounds are discussed and some assessment is made as to what additional investigations still need to be undertaken.

The regulation of cellular energy homeostasis within the CNS is crucial not only to neuronal survival, but to the brain's function as an integrator of hormonal and neural inputs that regulate many functions, such as feeding behavior. The sensing and regulation of CNS cellular energy balance is altered in many diseases. Recent studies have suggested that fatty acid metabolism plays a significant role in regulating cellular energy balance in the brain. This hypothesis is supported by observations that the pharmacological manipulation of fatty acid metabolism alters food intake and causes weight loss. Fatty acid levels are determined by fatty acid synthase (FAS), which catalyzes the de novo synthesis of longchain fatty acids that are stored as triglycerides during energy surplus, and carnitine palmitoyltransferase-1 (CPT-1), the rate-limiting enzyme for entry of long-chain acyl-CoA's into the mitochondria for fatty acid oxidation during energy deficit. Most recently, it has been reported that pharmacological manipulation of fatty acid metabolism can also alter cellular energy balance in a stroke model, thus providing neuroprotection. While the physiological contribution of fatty acid metabolism is a hypothesis that awaits further testing, here, we review studies from a number of laboratories investigating fatty acid metabolism as a therapeutic approach for obesity and disorders of CNS energy balance such as stroke.

The secretin/PACAP/VIP superfamily contains at least ten brain-gut peptides, including secretin, pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal polypeptide (VIP), glucagon, glucagon-like peptide-1 (GLP-1), glucagon like peptide-2 (GLP-2), gastric inhibitory polypeptide (GIP), peptide histidine isoleucine (PHI) or peptide histidine methionine (PHM), and growth hormone-releasing hormone (GHRH). These peptides exhibit a wide tissue distribution in the peripheral systems, indicating their pleiotrophic actions in the body. Meanwhile, their functions in the central nervious system (CNS) have also been consolidated recently. For instance, most of these peptides have shown to serve as neurotransmitters, neuromodulators, neurotrophic factors, and/or neurohormones in the brain, and hence, their potential as novel CNS agents in treating neurological disorders including Autism, Alzheimer's disease, Parkinson's disease and HIV-associated neuronal cell death were recently exploited. In this article, recent progress in research of peptides in this family with particular emphasis on structures, their central functions and potential use in the treatment of neuronal diseases are reviewed.

L-Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Termination of glutamate receptor activation and maintenance of low extracellular glutamate concentrations are mainly achieved by glutamate transporters (excitatory amino acid transporters 1-5: EAATs1-5) located in nerve endings and surrounding glia cells. Selective and potent inhibitors are needed to identify the physiological roles of transporters in the regulation of synaptic transmission or in the pathogenesis of neurological diseases. Glutamate or aspartate analogs such as threo-β-hydroxyaspartate (THA) and pyrrolidine dicarboxylate (PDC) derivatives have served as important experimental tools. Pharmacologically useful probes have emerged from modification of known inhibitors, such as threo-β- benzyloxyaspartate (DL-TBOA) which functions as a non-transportable blocker for all subtypes of EAATs. Nontransportable blockers are indispensable because, unlike substrates, they do not cause heteroexchange. By comparing the effects of substrates and non-transportable blockers, physiological roles of EAATs have been revealed. In this review, we will describe the functions of EAATs elucidated using these inhibitors. EAATs not only remove transmitter from synaptic clefts but also actively modulate neurotransmission. Moreover, high affinity ligands have been developed as novel pharmacological tools. TBOA analogs possessing a bulky substituent on their benzene ring significantly inhibited labeled glutamate uptake, the most potent of compound being (2S, 3S)-3-{3-[4-(trifluoromethyl)benzoyl-amino]benzyloxy}aspartate (TFB-TBOA). The pharmacological characterization of TFB-TBOA is also presented in this review.

The brain has traditionally been considered to be a target site of peripheral steroid hormones. By contrast, new findings over the past decade have shown that the brain itself also has the capability of forming steroids de novo from cholesterol, the so-called "neurosteroids". To understand neurosteroid action in the brain, data on the regio- and temporal- specific synthesis of neurosteroids are needed. Recently the Purkinje cell, a cerebellar neuron, has been identified as a major site for neurosteroid formation in the brain. Since this discovery, diverse actions of neurosteroids are becoming clear. The rat Purkinje cell actively synthesizes progesterone and 3α,5α-tetrahydroprogesterone (allopregnanolone) de novo from cholesterol during neonatal life, when cerebellar cortical formation occurs. Estrogen formation in this neuron may also occur in the neonate. Both progesterone and estradiol promote dendritic growth, spinogenesis and synaptogenesis via each cognate nuclear receptor in Purkinje neurons. We have used the Niemann-Pick type C (NP-C) mouse as a model for understanding neurosteroid action in the brain. NP-C is an autosomal recessive, childhood neurodegenerative disease characterized by defective intracellular cholesterol trafficking, resulting in Purkinje cell degeneration, as well as neuronal degeneration in other regions. Brains from adult NP-C mice contain less allopregnanolone than wild-type brain. Administration of allopregnanolone to neonatal NP-C mice increases Purkinje cell survival and delays neurodegeneration. Thus neurosteroid replacement therapy appears to be useful in ameliorating progression of the disease. Here we summarize the advances made in our understanding of the biosynthesis and actions of neurosteroids in the brain neuron. This review also describes medicinal impact of neurosteroids on neurodegenerative disease.