Graham Johnson

Convenient procedure for the preparation of alkyl and aryl substituted N-(aminoalkylacyl)sulfonamides

Abstract A convenient synthesis of N-(aminoalkylacyl)sulfonamides from CBZ potected glycine, β-alanine and GABA is described.

New preparations of the N-methyl-D-aspartate receptor antagonist, 4-(3-phosphonopropyl)-2-piperazinecarboxylic acid (CPP)

Two new methods to ensure selective alkylation of the N4 of 2-piperazinecarboxylic acid to give 4-(3-phosphonopropyl)-2-piperazinecarboxylic acid (CPP, 1) are reported. CPP can be conveniently prepared using a copper chelate to selectively protect the N1 position during alkylation. A second procedure uses methyl-4-BOC-1-CBZ-2-piperazinecarboxylate 5 as a versatile intermediate, which was further elaborated to CPP.

Synthesis and NMDA receptor binding of 2-amino-7,7-difluoro-7-phosphonoheptanoic acid

Abstract In an NMDA specific receptor binding assay, 1 has lower affinity than its parent, APH. This result suggests that for competitive antagonists, diionization of the phosphonic acid moiety may be detrimental to receptor affinity.

Chapter 2. Recent Advances In Excitatory Amino Acid Research

Publisher Summary This chapter discusses the recent advances across the spectrum of excitatory amino acid (EAA) research. The chapter also discusses the structure and mechanism of action of new EAA based therapeutic agents. EAAs have been shown to mediate a range of physiological functions, including nociception, vision, cardiovascular reflex, respiration, and motor control. EAAs have been suggested to play a role in the etiology of epilepsy. Competitive and non-competitive N-methyl-D-aspartic acid (NMDA) antagonists also have been shown to exert a protective action in animal models of anxiety. A central role for EAAs in stroke has been firmly established. The second messenger pathways, associated with EAA receptor activation, have been discussed in this chapter. NMDA receptor activation has been shown to stimulate the arachidonic acid cascade and induced proteolysis of brain spectrin. The AP4 (or APB) receptor is the least well characterized of the EAA receptors. But the NMDA receptor is the best characterized among them. The nature of interaction of the NMDA and phencyclidine (PCP) receptors has been defined, further using both receptor binding and electrophysiology. Binding of PCP site ligands are reported to be dependent on both NMDA receptor activation and membrane potential. From the high level of pharmaceutical interest in NMDA antagonists, increasing numbers of new antagonist structures have appeared. However, no deviations from the amino acid-spacer-phosphonic acid structural type have been reported. Dextromethorphan and MK-801 have been patented as an antineurotoxic agent. In addition, other opioids and nonopioids, including naloxone, have also been reported to protect against neurotoxicity in vitro . The stoichiometry of the glycine modulation of the NMDA receptor has been determined. It is clear that the foundation now exists to support rapid future progress in the area of excitatory amino acid research.

Synthesis of a cognition enhancing beta-lactam fused gamma-lactam

Abstract The preparation and cognition enhancing properties of a highly strained beta-lactam fused gamma-lactam are reported.

Synthesis and biological activity of conformationally constrained 4a-phenanthreneamine derivatives as noncompetitive NMDA antagonists

Abstract The syntheses, biological activity, and molecular modeling of conformationally constrained derivatives of cis-1,3,4,9,19,10a-hexahydro-N-methyl-4a(2H)-phenanthreneamine (PD 134365), a new conformationally rigid noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, are described.

Chapter 5 Recent Advances in Migraine Research

Publisher Summary The majority of chronic headaches are classified as classic and common migraine, cluster headache, and muscle contraction or tension headache. These are both bilateral and unilateral in nature and idiopathic in origin, and are collectively referred as vascular headaches. Although numerous studies have sought to define the etiology and pathophysiology of these conditions as separate entities, recent evidence is more supportive of a headache continuum, in which the headache types differ only in the severity of symptoms. The lack of agreement on both the precipitative factors and mechanisms by which headache pain is generated and perceived is evidenced in the numerous treatises on the subject. At present, migraine is more properly considered as a neurological disorder. A result of the complex and poorly understood pathophysiology of migraine is that no specific animal models have been reported. This lack of predictive models has resulted in the identification of effective drugs through an empirical clinical approach. The interpretation of such trials has frequently been hampered by a large placebo effect. This chapter briefly discusses the significant progress that has been made in understanding the mechanisms behind migraine pain generation and perception. Although past approaches to migraine prophylaxis have been essentially empirical in nature, recent advances in delineating pain-producing mechanisms and pathways offer the future promise of rational and targeted drug therapy of headache.

Chapter 11. Pharmacological Approaches in Acute Stroke

Publisher Summary Stroke is caused by an abrupt interruption in blood supply to part of the brain, resulting in ischemia and cerebral tissue necrosis. The interruption in cerebral blood flow is caused by an atherosclerotic arterial narrowing that develops progressively, but is of sudden hemodynamic significance or the abrupt lodging of an embolus within the cerebral circulation and its consequent, distal cerebral tissue ischemia. The treatment of acute stroke today consists mainly of individualized management dictated by diagnostic criteria and clinical predictors or outcome. Specific therapy for acute stroke includes normalization of systemic blood pressure, maintenance of vital functions and rehabilitation. Studies of experimental stroke in non-human primates have shown that surprisingly long episodes of cerebral ischemia can be tolerated without permanent disability and irreversible cerebral tissue injury, and, more importantly, that such tolerance is determined by the duration and degree of ischemia. Thus, thresholds of focal cerebral ischemia determine functional cellular activity and cerebral tissue viability. The clinical implications of the threshold concept are that in acute stroke pharmacological intervention that increases residual cerebral blood flow would be expected to lessen tissue injury and improve long-term functional outcome. Alternatively, treatment that enhances the brains tolerance to ischemic conditions would also be expected to benefit the acute stroke victim. This chapter discusses the pathophysiologic cascade of ischemic stroke, therapies that exemplify a pharmaceutical reduction in the cerebral tissues metabolic demand—hypothermia, barbiturates, anticonvulsants, ATP modifiers, oxyhemoglobin destabilizing agents, blood substitution. There is also a review of cerebral vasodilators, inhibitors of neuronal injury—antioxidants, iron chelators, excitatory amino acid antagonists, opiates, and chemotaxis inhibitors—and inhibitors of damaging ischemic metabolites—prostaglandins and leukotrienes. The chapter also explores other approaches to treatment such as antiedema agents, fibrinolytic agents, nootropic agents, hemorrheologic approaches, enhancers of neuronal plasticity, and lactic acidosis.