Paul S. Anderson

A super active cyclic hexapeptide analog of somatostatin

The cyclic hexapeptide, cyclo (Pro-Phe-D-Trp-Lys-Thr-Phe), I, has been shown to have the biological properties of somatostatin. We now report structure-activity studies which optimize the potency of this cyclic hexapeptide series with the synthesis of cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe), II, which is 50-100 times more potent than somatostatin for the inhibition of insulin, glucagon and growth hormone release. The hydroxyl group of tyrosine is seen to lend a 10-fold enhancement to the potency. Potency also is found to be correlated with hydrophobicity. II is found to improve the control of postprandial hyperglycemia in diabetic animals when given in combination with insulin. The analog is found to be quite stable in the blood and in the gastrointestinal tract, but the bioavailability after oral administration is only 1-3%. The biological properties and long duration of II should allow clinical evaluation of the inhibition of glucagon release as an adjunct to insulin in the treatment of patients with diabetes.

The Reduction of Nitrogen Heterocycles with Complex Metal Hydrides

Publisher Summary The reactions of complex metal hydrides occur by an attack of the nucleophilic hydride ion on an electrophilic center. Aromatic nitrogen heterocycles in which the nitrogen contributes only one electron to the π-system are electrophilic as compared to benzene, and show a reduction by lithium aluminum hydride, an active reducing agent. Thus, nitrogen heterocycles are more electrophilic than benzene and are susceptible to attack by the hydride ion from a complex metal hydride anion. In protic solvents the intermediate cyclic enamines can undergo further reduction. The proper choice of reducing agent and reaction conditions thus allow the preparation of many partially reduced nitrogen heterocycles unavailable by other routes. These reduction procedures provide a valuable adjunct to catalytic hydrogenation for the syntheses of saturated nitrogen heterocycles. This chapter provides examples of the various types of nitrogen heterocycles which have been investigated to provide a basis for evaluating this method of reduction in the synthesis of reduced and partially reduced nitrogen heterocycles.

N-trimethylsilylpyrroles as dienes in the synthesis of 1,4-dihydronaphthalen-1,4-imines and isoindoles†

A convenient, general synthetic method for 1,4-dihydronaphthaIen-1,4-imines via the Diels-Alder addition of benzyne to N-trimethylsilylpyrrole is described. The N-trimethylsilyl protecting group protected the product from secondary benzyne reactions and was easily removed. The use of a 1,3-dipolar reagent to convert 1,4-dihydronaphthalen-1,4-imines to isoindoles via a retro-Diels-Alder sequence is illustrated.

Chapter 6. Memory and Learning

Publisher Summary Although difficult to find traces, drugs are believed to have effect of memory and learning. Drug-induced changes in acquisition or extinction are interpreted to indicate that the drug has affected memory processes. However, the effectiveness of drugs that impair (retrograde amnesia) or facilitate (delay extinction) retention is sensitive to dose, type and degree of training, and time of drug administration. The recent trend has been to combine the behavioral results with biochemical measurements in an attempt to identify brain structures and systems that may be involved in the memory process. Many studies that have focused on measuring the consequences of electrical stimulation or microinjection of drugs into specific brain loci have shown that behaviorally-active drugs affect neurotransmitter systems, particularly noradrenergic and dopaminergic pathways. Studies in humans tend to corroborate the data in rodents. For example, administration of scopolamine to young students impaired memory storage and retrieval, as well as other cognitive functions. The impairment of cognitive function in both humans and primates was similar to that found in normal aged subjects. It has been shown that rats that are deficient in vasopressin have deficits in acquiring and maintaining avoidance behavior that can be corrected by treatment with this peptide. Interactions between opiate peptide systems and vasopressin pathways may also be of functional significance in memory processes. Experiments performed using subhuman species suggest that cholinomirnetic drugs should improve memory and cognition in humans who do not perform well, and this view is supported by many favorable clinical reports.

Design of cholecystokinin peptidomimetics

Abstract Cholecystokinin (CCK) is a polypeptide hormone which occurs in numerous molecular forms at various sites throughout the peripheral and central nervous systems. The wide range of physiological responses which have been attributed to CCK has stimulated the search for agents which mimic or block its action. Two principal CCK receptor subtypes have been characterized and numerous peptide substrate analogues have been identified which bind potently with these receptor subtypes. However, a number of insufficiencies inherent in peptide structures have limited their application as drugs. These shortcomings include rapid breakdown to inactive substances by proteases, poor transport, and rapid excretion. Such properties limit the duration of action and bioavailability of peptides and have prompted researchers to initiate the development of compounds which have less peptide character, indeed, to develop totally nonpeptidal agents. We describe the discovery of several potent non-peptide CCK antagonists which display selectivity versus the peripheral (CCK-A) and central (CCK-B) receptors. The most thoroughly characterized of these agents are the benzodiazepine derivatives MK-329 and L-365,260. These novel CCK antagonists are orally effective, long acting and devoid of agonist activity. MK-329 and L-365,260 should find widespread use in delineating the function of CCK receptors in human physiology and may have potential clinical application.