Daniel Lednicer

Effect of a butyrophenone derivative, U-32,802A, on brain biogenic amines

Abstract U-32,802A, a new butyrophenone derivative, was found to block the uptake of and to cause a release of 3 H-norepinephrine from the mouse heart. The releasing effect of U-32,802A was not blocked by pretreatment with protriptyline at 10 mg/kg. U-32,802A caused a severe and long-lasting depletion of mouse brain norepinephrine and dopamine with little effect on serotonin at a dose of 5 mg/kg i.p. U-32,802A also caused an increase in homovanillic acid in mouse striatum, a property common to a variety of antipsychotic agents. The spectrum of activity of U-32,802A is different from that of either haloperidol or reserpine and may represent a new class of amine-depleting agents.

4-ARYL-4-AMINOCYCLOHEXANONE DERIVATIVES: A CHEMICALLY NOVEL SERIES OF ANALGESICS INCLUDING OPIOID ANTAGONISTS AND EXTREMELY POTENT AGONISTS

Summary A structurally novel series of opioids has been synthesized and characterized biologically. These compounds are all derivatives of phenyl-cyclohexylamine. The structure-activity relationships (SARs) of this series are discussed as they pertain to the effects of phenyl substitutions, substitution in the 1 position of the cyclohexanone and alterations in the nitrogen substitution. Representatives of the hundreds of compounds synthesized are used to illustrate this SAR. Biological characterization includes in vivo analgesia, narcotic antagonism and narcotic behavioral effects, and in vitro 3 H-naloxone binding inhibition. Examination of these in vivo and in vitro SAR data suggests that p-halo substitutions optimize the ability of the compounds to gain access to the analgesic receptors, whereas m-OH substitution induces narcotic antagonist activity. The degree of antagonist activity may be decreased by lengthening the aminoalkyl substitution from methyl to pentyl. Remarkable increases in analgesic and 3 H-naloxone binding potency are induced by addition of a phenylethyl moiety to the 1 position of the cyclohexanone. These compounds have in vivo analgesic potencies up to 12,000 times that of morphine. Conformational commonalities between these latter compounds and the enkephalins are discussed.

Chapter 26. Reactions of Interest in Medicinal Chemistry

Publisher Summary Various literatures in organic chemistry have already established significant reactions that are quite useful in medicinal chemistry. There are 70 odd transforms that can offer more convenient access to important functional arrays because they lead to moieties. The discussion includes many useful organic processes, such as “Asymmetric Syntheses,” “New applications of Malononitrile in Organic Synthesis,” “Intramolecular Ene Reaction in Organic Synthesis,” “α-Sulfenylated Carbonyl Compounds in Organic Synthesis,” etc. A new method for transposition of carbonyl groups starts by interception of the intermediate from tosyl hydrazone decomposition with Me 3 SiCl. Another new method for dehydrogenation of carbonyl compounds consists of conversion to their pyridine-2-sulfide derivatives, followed by oxidation (MCPBA), and by mild heat. This chapter also discusses the recent development of dienes incorporating latent functionality has greatly expanded the utility of Diels Alder approaches to synthesis of complex molecules. Pyrolytic scission of cyclobutenes leads to a diene that promises to be useful in a Diels Alder approach to catechols. Heating of the silyl derivative of the acyloin product from dimethyl glutarate in the presence of dienophiles affords adducts of the transient diene. A general procedure has been developed for the preparation of 1,4-di-hydrothiophene-3-carboxylates starting from acetaldehyde-2-thiol. The unprotected carbonyl group can be condensed with anions to afford products that give substituted phenylacetic acid derivatives on aromatization. A versatile nonFriedel–Crafts approach to naphthols is provided by condensation of the toluic acid sulfoxide with substituted acrylates or methyl vinyl ketone. Sequential conjugate addition and acylation of the first formed anion leads to tetralone. A related scheme that leads to hydroxytetralones involves reaction of the anion from a phthalide (LDA) with an unsaturated ester. This reaction too involves a conjugate addition-acylation sequence.

Chapter 19. Reproduction

Publisher Summary The means for chemical contraception are now available, with various estrogen progestin regimes. Considerable clinical and biological effort is devoted to find new and more convenient means of employing these hormonal agents. The success achieved with post coitally administered estrogens may lead to a post coital pill. In the female, for example, it is possible to prevent ovulation, sperm capacitation, and transport of that sperm to the oviduct, penetration of the egg by sperm, division of the fertilized egg, transport of the egg to the uterus, or even nidation. The developmental process of the male germ cell from the spermatogonium to a mature sperm cell also appears to offer numerous points of attack. Despite this, the only practical means of chemical contraception as presently available consists of estrogen progestin type of oral contraceptives. Though much effort has been expended in the search for some means of contraception that does not involve the pituitary, such an agent has not yet been found. Despite a large amount of both chemical and biological work on compounds that may be loosely termed estrogen antagonists, no notice of clinical success of such an agent has as yet appeared. An ideal agent for achieving contraception would be a drug that completely bypasses the endocrine system; this breakthrough is still to come.