[D-Ala2]-Met-enkephalinamide (DALA), a synthetic enkephalin analog designed by in vitro analysis, binds to opiate receptors almost as tightly as methionine-enkephalin. Since it is not susceptible to degradation by brain enzymes, low doses (5 to 10 micrograms) cause profound, long-lasting, morphine-like analgesia when microinjected into rat brain.

http://science.sciencemag.org/content/sci/194/4262/330.full.pdf

(D-Ala2)-Met-enkephalinamide: a potent, long-lasting synthetic pentapeptide analgesic

Cyclic nucleotide phosphodiesterases: Pharmacology, biochemistry and function

The extract of the opium poppy is among the oldest materials used for medicinal purposes, and the study of the major alkaloid in this extract, morphine. is one of the oldest areas of biological research. Our lack of understanding on the molecular level of how morphine and its analogues produce their effects may be in large part related to the fact that they exert most of their actions on the central nervous system. the most complex organ in animals and man. The opiates produce a large variety of pharmacological responses, the most important of which are analgesia. euphoria, and addiction. The latter includes the development of tolerance and physiological and psychological dependence. The discovery of opiate receptors in the central nervous system of animals and man and the resulting discovery of endogenous opiate-like ligands for these receptors (discussed in this issue by L. Terenius and introduced briefly in this review) have given rise to considerable activity and excite­ ment in the field of opiate research. In this review we attempt to cover. within the limitations of space, the most significant advances in our knowledge of opiate receptors since their discovery.

The opiate receptors.

which are found in significant amounts in nearly every prokaryotic and eukaryotic cell type. Despite the ubiquitous nature of these compounds, the precise roles that polyamines play in cellular physiology are still being defined, with new avenues for research arising continuously. As a result, there are active research programs focusing on polyamine metabolism in an extremely diverse set of disciplines. The pathways for polyamine metabolism have been elucidated for a relatively small number of organisms. There are important interspecies differences in polyamine metabolism, especially between eukaryotic cells, plants, and some bacteria and protozoa. In some prokaryotes, only putrescine and spermidine are synthesized, while in other cases, such as certain thermophilic bacteria, polyamines with chains longer than spermine are found. In some parasitic organisms, there are additional enzymes which are not present in the host cell and, as such, provide a target for the design of specific antiparasitic agents. However, the enzymes involved in human and mammalian polyamine metabolism are reasonably similar, and inhibitors targeted to these enzymes rely on the observation that polyamine metabolism is accelerated and polyamines are required in higher quantities, in target cell types. The diversity of biological research in the polyamine field is the subject of an excellent book by Seymour Cohen.1 This Perspective will deal with the use of polyamine analogues as chemotherapeutic agents, i.e., the use of synthetic polyamine analogues as anticancer or antiinfective agents. The reader should be aware of additional areas of polyamine research (polyamines as modulators of the NMDA receptor, polyamine-based venoms, polyamines as potential carriers for drug delivery, polyamines used in boron-neutron capture therapy, etc.) which are beyond the scope of this review. The polyamine pathway represents an important target for chemotherapeutic intervention, since depletion of polyamines results in the disruption of a variety * Address correspondence to: Patrick M. Woster, Ph.D, Dept. of Pharmaceutical Sciences, 539 Shapero Hall, Wayne State University, Detroit, MI 48202. Tel: 313-577-1523. Fax: 313-577-2033. E-mail: woster@wizard.pharm.wayne.edu. † Johns Hopkins Oncology Center. § Wayne State University. Figure 1. Structures of the natural polyamines: putrescine (1), spermidine (2), and spermine (3). © Copyright 2001 by the American Chemical Society

Terminally alkylated polyamine analogues as chemotherapeutic agents

Opiate receptor affinities and behavioral effects of enkephalin: Structure-activity relationship of ten synthetic peptide analogues

Benz-fused mesoionic xanthine analogues as inhibitors of cyclic-AMP phosphodiesterase.

For a homologous series of N-alkylnorketobemidones a statistically significant correlation was found between the relative abilities to bind mouse brain homogenate in vitro and their in vivo mouse hot-plate analgesic potencies. The correlation between in vitro binding in the presence of 100 mM sodium and analgesic potency was not as good AS THAT as that found in the absence of sodium. A statistically significant correlatin was found between thir analgesic potencies and their abilities to antogonize electrically induced contractions of the guinea pig ileum.

Homologous N-alkylnorketobemidones. Correlation of receptor binding with analgesic potency.

Several simple alkyl and aralkyl derivatives of mesoionic thiazolopyrimidines (1) and mesoionic 1,3,4-thiadiazolopyrimidines (2) were found to possess theophylline-like activity as inhibitors of cyclic-AMP phosphodiesterase (PDE). Reduction of the C2-C3 double bond of 1 or replacement of the sulfur atom of 1 or 2 with an N-methyl group nearly abolishes activity. Optimal activity appears to be associated with a hydrophobic substituent at the N8 position. The five-membered ring of 1 can be replaced by a pyridine or isoquinoline nucleus without untoward effects. Preliminary kinetic data suggest that the type of enzyme inhibition produced by the mesoionic derivatives is similar to that observed for theophylline. Thus, several novel mesoionic ring systems display activity as inhibitors of cyclic-AMP PDE and can serve as lead compounds for further investigation.

Mesoionic purinone analogues as inhibitors of cyclic-AMP phosphodiesterase: a comparison of several ring systems.

2,9 alpha-Dimethyl-5-(m-hydroxyphenyl)morphan (3a) has been synthesized from 5-(m-methoxyphenyl)-2-methyl-9-oxomorphan (4) and resolved into its enantiomers (+)-3a and (-)-3a. The assigned alpha-orientation of the 9-methyl group was derived from studies of induced NMR shifts using Eu(fod)3-d27. Compound (+)-3a has inappreciable agonist (antinociceptive) activity in mice, and (-)-3a shows codeine-like potency in the hot-plate and writhing tests only. The 9-demethyl homologues, (+)-1 and (-)-1, are strong agonists, about as potent as morphine in these tests as well as in the tail-flick assay. The racemic compound 3a and (+)-3a, but not (-)-3a, exhibit low-potency, narcotic-antagonist activity in mice (tail-flick test, vs. morphine). All three, however, precipitate abstinence in nonwithdrawn, morphine-dependent rhesus monkeys. Monkey studies with the 9-demethyl homologues confirmed earlier results showing that (+)-1, suppressing abstinence in withdrawn animals, has high physical dependence capacity, while (-)-1 has none. Instead, (-)-1 precipitates abstinence in nonwithdrawn animals. Studies in rats and isolated organs (guinea pig ileum and mouse vas deferens) and receptor-binding assays confirm the quite different opioid-action profiles of (+)-1 and (-)-1, which thus might interact with different opioid receptors. Catalytic hydrogenation of the methiodide (7) of 5 gave, instead of the expected epimer of 3a, ring-opened compound 8.

Racemic and optically active 2,9-dimethyl-5-(m-hydroxyphenyl)morphans and pharmacological comparison with the 9-demethyl homologues.

In an effort to increase the specificity of the potent phosphodiesterase inhibitor papaverine, we synthesized two series of novel 1-(4-aminobenzyl)- and 1-(4-aminophenyl)isoquinoline derivatives, incorporating alkylating moieties on the amine substituents. These compounds were evaluated for their inhibitory action on phosphodiesterase preparations from bovine heart and rat cerebral cortex. Studies were also conducted to determine whether these compounds were reacting with the enzymes in an irreversible manner. The compounds were potent inhibitors of the phosphodiesterases; however, no evidence was found for an irreversible inhibition.

1-(4-Aminobenzyl)-and 1-(4-aminophenyl)isoquinoline derivatives: synthesis and evaluation as potential irreversible cyclic nucleotide phosphodiesterase inhibitors.

Michael E. Rogers

Papers

Benz-fused mesoionic xanthine analogues as inhibitors of cyclic-AMP phosphodiesterase.

Homologous N-alkylnorketobemidones. Correlation of receptor binding with analgesic potency.

Mesoionic purinone analogues as inhibitors of cyclic-AMP phosphodiesterase: a comparison of several ring systems.

Racemic and optically active 2,9-dimethyl-5-(m-hydroxyphenyl)morphans and pharmacological comparison with the 9-demethyl homologues.

1-(4-Aminobenzyl)-and 1-(4-aminophenyl)isoquinoline derivatives: synthesis and evaluation as potential irreversible cyclic nucleotide phosphodiesterase inhibitors.