https://www.cell.com/cell/pdf/S0092-8674(00)81965-0.pdf

The Sleep Disorder Canine Narcolepsy Is Caused by a Mutation in the Hypocretin (Orexin) Receptor 2 Gene

The family of voltage-gated sodium channels initiates action potentials in all types of excitable cells. Nine members of the voltage-gated sodium channel family have been characterized in mammals, and a 10th member has been recognized as a related protein. These distinct sodium channels have similar structural and functional properties, but they initiate action potentials in different cell types and have distinct regulatory and pharmacological properties. This article presents the molecular relationships and physiological roles of these sodium channel proteins and provides comprehensive information on their molecular, genetic, physiological, and pharmacological properties.

https://pharmrev.aspetjournals.org/content/pharmrev/57/4/411.full.pdf

International Union of Pharmacology. XLVIII. Nomenclature and Structure-Function Relationships of Voltage-Gated Calcium Channels

The suite of currently used drugs can be divided into two categories - traditional 'small molecule' drugs with typical molecular weights of 5000 Da that are not orally bioavailable and need to be delivered via injection. Due to their small size, conventional small molecule drugs may suffer from reduced target selectivity that often ultimately manifests in human side-effects, whereas protein therapeutics tend to be exquisitely specific for their targets due to many more interactions with them, but this comes at a cost of low bioavailability, poor membrane permeability, and metabolic instability. The time has now come to reinvestigate new drug leads that fit between these two molecular weight extremes, with the goal of combining advantages of small molecules (cost, conformational restriction, membrane permeability, metabolic stability, oral bioavailability) with those of proteins (natural components, target specificity, high potency). This article uses selected examples of peptides to highlight the importance of peptide drugs, some potential new opportunities for their exploitation, and some difficult challenges ahead in this field.

The Future of Peptide‐based Drugs

A monograph communicating the current realities and future possibilities of unifying basic studies on anatomy and cellular physiology with investigations of the behavioral and physiological events of waking and sleep. Steriade established the Laboratory of Neurophysiology at Laval U., Quebec; McCarl

Brainstem control of wakefulness and sleep

Drug discovery from marine natural products has enjoyed a renaissance in the past few years. Ziconotide (Prialt; Elan Pharmaceuticals), a peptide originally discovered in a tropical cone snail, was the first marine-derived compound to be approved in the United States in December 2004 for the treatment of pain. Then, in October 2007, trabectedin (Yondelis; PharmaMar) became the first marine anticancer drug to be approved in the European Union. Here, we review the history of drug discovery from marine natural products, and by describing selected examples, we examine the factors that contribute to new discoveries and the difficulties associated with translating marine-derived compounds into clinical trials. Providing an outlook into the future, we also examine the advances that may further expand the promise of drugs from the sea.

Drug development from marine natural products

Objective The objective was to assess the analgesic, antihyperesthesic, and anti-allodynic properties of SNX-111 in neuropathic pain. Design We describe a patient with refractory, severe deafferentation pain successfully treated with SNX-111 in an open-label, baseline-controlled Phase I/II trial. Setting The patient was hospitalized for treatment and observation. Patient The patient was a 43-year-old man with intractable deafferentation pain of 23 years' duration secondary to brachial plexus avulsion. Intervention SNX-111, the first neuron-specific, N-type, voltage-sensitive calcium channel blocker developed for clinical use, was administered by continuous, constant-rate, intrathecal infusion via an indwelling cervical catheter. Outcome measures The primary outcome measures were the Visual Analog Scales of Pain Intensity (VASPI) and Pain Relief (VASPR). Results The patient experienced complete pain relief (VASPI = 0.0 cm and VASPR = 10.0 cm) with elimination of hyperesthesia and allodynia. Conclusions SNX-111, administered intrathecally by continuous, constant-rate infusion, produced dose-dependent pain relief in a 43-year-old male patient with a 23-year history of intractable deafferentation and phantom limb pain secondary to brachial plexus avulsion and subsequent amputation. Dizziness, blurred vision, and lateral-gaze nystagmus were dose-dependent side effects that resolved with decreasing dose levels. Complete pain relief was achieved in this patient without side effects after dose adjustment. We conclude that SNX-111 is a potent analgesic, antihyperesthesic, and antiallodynic agent. Controlled studies of SNX-111 in patients with malignant and nonmalignant pain syndromes are warranted and are under way.

Use of intrathecal SNX-111, a novel, N-type, voltage-sensitive, calcium channel blocker, in the management of intractable brachial plexus avulsion pain.

Pharmacotherapeutic potential of omega-conotoxin MVIIA (SNX-111), an N-type neuronal calcium channel blocker found in the venom of Conus magus.

The role of the muscarinic cholinergic receptor in narcolepsy was examined using radioligand binding to various brain regions of normal and genetically narcoleptic Doberman pinschers. In this multi-litter study, a previous report of a proliferation of muscarinic cholinergic receptors in the brainstem was confirmed, and the concentration of the M2 receptor subtype, in particular, was elevated. This up-regulation of brainstem cholinergic receptors suggests a problem with release of acetylcholine, which, together with previous reports of an impairment of dopamine release, may be indicative of a fundamental membrane problem in narcolepsy.

/pdf/muscarinic-cholinergic-receptors-and-the-canine-model-of-axsaauym5u.pdf

Muscarinic cholinergic receptors and the canine model of narcolepsy.

SNX-111 is the first neuronal N-type, voltage-sensitive calcium channel (VSCC) blocker to enter clinical drug development. Areas of potential therapeutic utility include treatment of nociceptive and neuropathic pain and neuroprotection after ischemic brain injury. The data presented demonstrate that SNX-111 is biologically active in humans and indicate for the first time a neurophysiologic function of N-type VSCCs in humans.

S. Scott Bowersox

Papers

Use of intrathecal SNX-111, a novel, N-type, voltage-sensitive, calcium channel blocker, in the management of intractable brachial plexus avulsion pain.

Pharmacotherapeutic potential of omega-conotoxin MVIIA (SNX-111), an N-type neuronal calcium channel blocker found in the venom of Conus magus.

Muscarinic cholinergic receptors and the canine model of narcolepsy.

Sympatholysis after neuron-specific, N-type, voltage-sensitive calcium channel blockade: first demonstration of N-channel function in humans.

Biogenic amine concentrations in the brains of normal and narcoleptic canines: current status.