Annual Review of Pharmacology and Toxicology

Subtypes of neuronal nicotinic acetylcholine receptors (nAChRs) are constructed from numerous subunit combinations that compose channel-receptor complexes with varied functional and pharmacological characteristics. Structural and functional diversity and the broad presynaptic, postsynaptic, and nonsynaptic locations of nAChRs underlie their mainly modulatory roles throughout the mammalian brain. Presynaptic and preterminal nicotinic receptors enhance neurotransmitter release, postsynaptic nAChRs contribute a small minority of fast excitatory transmission, and nonsynaptic nAChRs modulate many neurotransmitter systems by influencing neuronal excitability. Nicotinic receptors have roles in development and synaptic plasticity, and nicotinic mechanisms participate in learning, memory, and attention. Decline, disruption, or alterations of nicotinic cholinergic mechanisms contribute to dysfunctions such as epilepsy, schizophrenia, Parkinson's disease, autism, dementia with Lewy bodies, Alzheimer's disease, and addiction.

During the past few years, crystallography of G protein–coupled receptors (GPCRs) has experienced exponential growth, resulting in the determination of the structures of 16 distinct receptors—9 of them in 2012 alone. Including closely related subtype homology models, this coverage amounts to approximately 12% of the human GPCR superfamily. The adrenergic, rhodopsin, and adenosine receptor systems are also described by agonist-bound active-state structures, including a structure of the receptor–G protein complex for the β₂-adrenergic receptor. Biochemical and biophysical techniques, such as nuclear magnetic resonance and hydrogen-deuterium exchange coupled with mass spectrometry, are providing complementary insights into ligand-dependent dynamic equilibrium between different functional states. Additional details revealed by high-resolution structures illustrate the receptors as allosteric machines that are controlled not only by ligands but also by ions, lipids, cholesterol, and water. This wealth of data is helping redefine our knowledge of how GPCRs recognize such a diverse array of ligands and how they transmit signals 30 angstroms across the cell membrane; it also is shedding light on a structural basis of GPCR allosteric modulation and biased signaling.

The mechanisms of general anesthesia in the central nervous system are finally yielding to molecular examination. As a result of research during the past several decades, a group of ligand-gated ion channels have emerged as plausible targets for general anesthetics. Molecular biology techniques have greatly accelerated attempts to classify ligand-gated ion channel sensitivity to general anesthetics, and have identified the sites of receptor subunits critical for anesthetic modulation using chimeric and mutated receptors. The experimental data have facilitated the construction of tenable molecular models for anesthetic binding sites, which in turn allows structural predictions to be tested. In vivo significance of a putative anesthetic target can now be examined by targeted gene manipulations in mice. In this review, we summarize from a molecular perspective recent advances in our understanding of mechanisms of action of general anesthetics on ligand-gated ion channels.

Orexin-A and -B (also known as hypocretin-1 and -2) are neuropeptides produced in the lateral hypothalamus that promote many aspects of arousal through the OX1 and OX2 receptors. In fact, they are necessary for normal wakefulness, as loss of the orexin-producing neurons causes narcolepsy in humans and rodents. This has generated considerable interest in developing small-molecule orexin receptor antagonists as a novel therapy for the treatment of insomnia. Orexin antagonists, especially those that block OX2 or both OX1 and OX2 receptors, clearly promote sleep in animals, and clinical results are encouraging: Several compounds are in Phase III trials. As the orexin system mainly promotes arousal, these new compounds will likely improve insomnia without incurring many of the side effects encountered with current medications.

The unabated rise in the prevalence of obesity is a challenge for global health care systems. Efforts to reverse this trend by dietary or behavioral counseling have not been successful, which has stimulated efforts to find a role for pharmacotherapy. Currently only a small number of antiobesity drugs are approved for long-term use and only a few compounds are in clinical development. Despite recent progress in the understanding of the regulation of energy balance, drug discovery has been less productive than expected. In the present review, the clinically available antiobesity agents are discussed. Examples of drug candidates that are currently in development are given and the possible future range of antiobesity agents is illustrated by the targets being addressed in drug discovery. Finally, the efficacy of antiobesity agents and their value in the treatment of obesity are assessed in comparison with other therapeutic approaches, such as surgery and changes in lifestyle.

The cytosolic selenoprotein thioredoxin reductase 1 (TrxR1, TXNRD1), and to some extent mitochondrial TrxR2 (TXNRD2), can be inhibited by a wide range of electrophilic compounds. Many such compounds also yield cytotoxicity toward cancer cells in culture or in mouse models, and most compounds are likely to irreversibly modify the easily accessible selenocysteine residue in TrxR1, thereby inhibiting its normal activity to reduce cytosolic thioredoxin (Trx1, TXN) and other substrates of the enzyme. This leads to an oxidative challenge. In some cases, the inhibited forms of TrxR1 are not catalytically inert and are instead converted to prooxidant NADPH oxidases, named SecTRAPs, thus further aggravating the oxidative stress, particularly in cells expressing higher levels of the enzyme. In this review, the possible molecular and cellular consequences of these effects are discussed in relation to cancer therapy, with a focus on outstanding questions that should be addressed if targeted TrxR1 inhibition is to be further developed for therapeutic use.

▪ Tóm tắt: Khoảng giữa cho đến cuối thập niên 1980, các nghiên cứu đã được công bố chứng minh sự tồn tại của các thụ thể glutamate không phải là kênh cation điều khiển ligan mà được kết nối với hệ thống hiệu ứng thông qua các protein liên kết với GTP. Kể từ những báo cáo ban đầu đó, đã có sự tiến bộ vượt bậc trong việc đặc trưng hóa các thụ thể glutamate metabotropic (mGluRs), bao gồm việc nhân bản và đặc trưng hóa cDNA mã hóa cho một họ gồm tám kiểu thụ thể mGluR, trong số đó có một số loại phân cắt khác nhau. Cũng có sự tiến bộ vượt bậc trong việc phát triển mới các chất chủ vận và chất đối kháng mGluR đặc hiệu cao, và hướng đến xác định vai trò sinh lý của các mGluR trong não động vật có vú. Những phát hiện này có những triển vọng thú vị đối với việc phát triển thuốc và cho thấy rằng các mGluR cung cấp một mục tiêu mới cho phát triển các tác nhân điều trị có thể có tác động đáng kể lên dược lý thần kinh.