Current Pharmaceutical Design - Volume 9, Issue 8, 2003

L-Glutamate is the major excitatory neurotransmitter in mammalian central nervous system, and excitatory amino acid transporters (EAATs) are essential for terminating synaptic excitation and for maintaining extracellular glutamate concentration below toxic levels. Although the structure of these channel-like proteins has not been yet reported, their membrane topology has been hypothesised based on biochemical and protein sequence analyses. In the case of an inadequate clearance from synaptic cleft and from the extrasynaptic space, glutamate behaves as a potent neurotoxin, and it may be related to several neurodegenerative pathologies including epilepsy, ischemia, amyotrophic lateral sclerosis, and Alzheimer disease. The recent boom of glutamate is demonstrated by the enormous amount of publications dealing with the function of glutamate, with its role on modulation of synaptic transmission throughout the brain, mainly focusing: i) on the structure of its receptors, ii) on molecular biology and pharmacology of Glu transporters, and iii) on the role of glutamate uptake and reversal uptake in several neuropathologies. This review will deal with the recent and most interesting published results on Glu transporters membrane topology, Glu transporters physiopathological role and Glu transporters medicinal chemistry, highlighting the guidelines for the development of potential neuroprotective agents targeting neuronal high-affinity sodium-dependent glutamate transporters.

Energy balance is a highly regulated, complex process which is modulated by central and peripheral systems. Dysregulation of energy homeostasis can result in metabolic disorders, such as obesity and type II diabetes. Obesity and type II diabetes are two of the most prevalent and challenging clinical conditions in society today. A growing body of evidence has implicated the melanocortin system as an important component in the maintenance of energy balance. α- MSH, a 13 amino acid peptide secreted as a product of the pro-opiomelanocortin (POMC) gene in the pituitary is a potent agonist of 4 of the 5 cloned melanocortin receptors (MCR). MC receptors are members of a G-protein-coupled receptor (GPCR) family, which signal through cAMP. Agouti and agoutirelated protein (AGRP) are natural antagonists of melanocortin receptors and participate in regulation of skin / fur pigmentation, body weight, and adiposity. Stimulation of MC receptors has pleiotropic effects, which impact the nervous system as well as endocrine and immune functions. One of the most prominent effects of MC receptor stimulation is a dramatic suppression of food intake and body weight, which has led to the hypothesis that the MC receptor system plays a primary role in the maintenance of energy balance. This idea is supported by a large body of pharmacological, molecular and human genetic evidence. The following review summarizes the role of melanocortin receptors in the regulation of food intake and energy homeostasis and highlights the opportunities for MC receptors as drug development targets in treating eating disorders and diabetes.

The dopamine D3 receptor has been the subject of a tremendous amount of research since its discovery in 1990. A previous review of this subject [3] described the advances in molecular biology and neuroanatomical localization of the D3 receptor, with a special emphasis on schizophrenia. In the current review, we attempt to describe recent advances in the biochemistry and pharmacology of the D3 receptor from the molecular to the behavioral level. Evidence linking an alteration in D3 receptor function as playing an important role in the etiology of a variety of CNS disorders, including schizophrenia, Parkinson's Disease, and substance abuse is also provided. Also discussed are the recent developments in attempting to map the ligand-binding domains of the D2 and D3 receptors. A. survey of the literature, including a description of the medicinal chemistry approaches toward developing D3-selective ligands, is also presented in this review.

[123I]Epidepride, [18F]fallypride, and [76Br]isoremoxipride (FLB-457) and their corresponding [11C]labeled derivatives belong to a class of high-affinity radioligands for SPECT or PET imaging of dopamine D2 receptors in the human brain. In contrast to previously used imaging agents, these ligands are capable of identifying extrastriatal dopamine D2 receptors. The design of these substituted benzamides derive its origin from the atypical antipsychotic agent, remoxipride. Starting in the late 1970's, halogenated analogs of (S)-sulpiride were evaluated in binding assays and behavioral studies, leading to the discovery of remoxipride. Remoxipride was 10 times weaker than sulpiride in vitro but 50 times more potent in vivo. Search for a putative active metabolite of remoxipride led to the discovery of raclopride and eticlopride, the former becoming a useful radioligand as tritium or carbon-11 labeled form for receptor binding and PET studies, respectively. In the US, the mono-iodine analog of raclopride, [123I]iodobenzamide (IBZM), was found to have moderate putamen-to-cerebellum ratio in rat and human brain. Continued search for metabolites of remoxipride led to the discovery of its 3,6-dihydroxy derivative, NCQ-344, with an extremely potent in vivo activity in the rat. SAR studies of the metabolites of remoxipride led to the discovery of the 3- methoxy isomer, isoremoxipride (FLB-457) and its corresponding 6-hydroxy analog, FLB-463, both having affinities for the dopamine D2 receptor in the 20-30 pM range. Later, the 5-[123I]iodo analog of FLB-463, [123I]ioxipride ([123I]NCQ- 298), became a potential SPECT imaging agent. In the mean time, the deshydroxy analog of IBZM, [125I]iodopride, showed binding potential in the rat similar to [125I]IBZM. Epidepride was designed by combining the structure of isoremoxipride with that of iodopride. In 1988, epidepride was independently prepared and radiolabeled in three separate laboratories in Stockholm, Berkeley, and Nashville. Evaluation of seven [125I]iodine substituted analogs of raclopride, including IBZM, revealed the unusual high striatum-to-cerebellum ratio of 234 of [125I]epidepride in the rat. Subsequent SPECT images with [123I]epidepride demonstrated its ability to identify extrastriatal dopamine D2 receptors in the human brain. Exploration of the structure of epidepride confirmed its exceptional properties, to be exceeded only by its N-allyl homolog, [125I]nalepride. The design by others of a series of potent 5-(3-[18F]fluoropropyl) substituted analogs of epidepride for PET imaging, lead to the discovery of [18F]fallypride. By elucidating the role of lipophilicity in the substituted benzamides, the excellent imaging characteristics of [11C] / [123I]epidepride, [11C] / [76Br]isoremoxipride and [18F]fallypride, could not only be explained but predicted with remarkable accuracy. By using the inverse product of the receptor affinity (KD), and the apparent partition constant of the radioligand (P(7.4)), estimates of maximal binding potential of any radioligand for imaging of any neurotransmitter receptor or transporter site seem possible.