A series of chiral interphenylene 7-oxabicyclo[2.2.1]heptane semicarbazones 19-26 were prepared and evaluated for their in vitro thromboxane (TxA2) antagonistic activity and in vivo duration of action. The potency of 19-26 was found to highly dependent on the substitution pattern of the interphenylene ring and decreased in the order ortho greater than meta much greater than para. SQ 35,091 (25), [1S-(1 alpha,2 alpha,3 alpha,4 alpha)]-2-[[3-[[[(phenylamino) carbonyl]hydrazono]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl] benzenepropanoic acid, was identified as a potent and long-acting TxA2 antagonist. In human platelet rich plasma SQ 35,091 inhibited arachidonic acid (800 microM) and U-46,619 (10 microM) induced aggregation with I50 values of 3 and 12 nM, respectively. In contrast, no inhibition of ADP (20 microM) induced aggregation was observed at greater than 1000 microM. Receptor binding studies with [3H]-SQ 29,548 showed SQ 35,091 was a competitive antagonist with a Kd value of 1.0 +/- 0.1 nM in human platelet membranes. In vivo SQ 35,091 (0.2 mg/kg po) showed extended protection (T50 = 16 h) from U-46,619 (2 mg/kg iv) induced death in mice. These compounds have for the first time demonstrated that a metabolically stable interphenylene alpha-sidechain can be introduced into a prostanoid-like series of TxA2 antagonists with the maintainance of potent antagonistic activity.

Experiments were conducted in pentobarbital anesthetized dogs to investigate the effects of captopril on sympathetic neuronal control of the heart and hindlimb vasculature. Captopril, 3.1 mg/kg, i.v. produced marked reductions in blood pressure and hindlimb perfusion pressure, an observation consistent with the high plasma renin activity in the test animals. Increments in hindlimb perfusion pressure elicited by electrical stimulation of the lumbar sympathetic chain were also significantly reduced following captopril administration (p less than .002). The subsequent administration of a ten fold higher dose of captopril, 31.0 mg/kg, produced no further attenuation of the neurally mediated responses. In contrast to the decreased vascular responses to nerve stimulation after captopril, the tachycardia produced by stimulation of pre- or post-ganglionic neurons to the stellate ganglion were not altered. The results of the present study suggest that captopril acts by inhibiting vascular sympathetic neuronal function when the activity of the renin-angiotensin system is elevated. The attenuation of neurally mediated vasoconstriction may be due to the interruption of angiotensin II formation, thereby, preventing the facilitatory effects of angiotensin on sympathetic neurons.

Kidney renin concentrations were significantly lower in spontaneously hypertensive rats (SHR) than in normotensive Wistar Kyoto (WKY) rats. After treatment of both SHR and WKY rats with captopril (100 mg/kg p.o. for 3 months), kidney renin concentration increased dramatically in SHR and slightly, but significantly, in WKY. After captopril treatment, kidney renin content of SHR was still significantly lower than WKY. Because of the lower content of kidney renin in SHR and the proportionately greater increase in kidney renin content in SHR after captopril treatment than in WKY, it is proposed that a fundamental difference(s) in the control of the renin-angiotensin system exists in SHR, an effect which may or may not be related to SHR hypertension.

On the basis of the data reported here, one may conclude that although many agents that act in the central nervous system are modulators of the action of cyclic AMP, it is difficult to establish a direct connection between the pharmacologic activity and the levels of cyclic AMP in the brain. This lack of interrelation applies to the benzodiazepines as well as to the pyrazolopyridines. The data for members of the latter group are somewhat frustrating in this regard, since an excellent correlation has been shown to exist between the potency of inhibition of PDE and activity in the antianxiety test. In measurements of steroidogenesis in the isolated adrenal cell, the correlation between activity in vito and the conflict assay is even better. The data presented here and reported elsewhere (Shimizu et al., 1974; Kelly et al., 1974; Mayer and King, 1974; King and Mayer, 1974) provide evidence that agents that act as inhibitors of PDE in cell-free systems exert their influence on cyclic AMP in tissue slices of the brain of guinea pigs by mechanisms that seem not to be related to an effect on PDE. Papaverine, and possibly chlordiazepoxide, may act by releasing agonists that, in turn, stimulate the accumulation of cyclic AMP. This activity is blocked bo other inhibitors of PDE, such as theophyline. Results obtained by the use of platelets are refreshingly clear. Inhibition of aggregation has been shown to occur when the level of cyclic AMP is raised, and a suggestive exists that the most potent inhibitors of platelet PDE are the best potentiators of the action of PGE1 in blocking aggregation. The study utilizing drugs collected from a large number of therapeutic classes makes clear that it is difficult to attribute the mechanism of action for any of the classes studied to modulation of cyclic AMP. An unexpected finding of this study, however, was the fact that pharmacologic agents include an unusually large number of inhibitors of PDE as compared with agents chosen at random. This finding provides a powerful tool for the biochemical pharmacologist who is examining large numbers of compounds in the search for potential drugs.

A series of cyclic 2′,3′-nucleotides, cyclic 3′,5′-nucleotides and derivatives of cyclic 3′,5′-adenosine monophosphate (cyclic AMP) with a substituent at the C-8 position were investigated as inhibitors of partially purified cyclic AMP phosphodiesterases (PDE) of cat heart and rat brain. The assays were carried out at a substrate concentration (0.06 μM) where the contribution to the total enzyme activity by phosphodiesterases with Km values for cyclic AMP above 100 μM was insignificant; consequently the activity measured was that of low Km enzymes.

This chapter discusses studies focusing on agents that affect cyclic AMP (cAMP)levels. An extensive study of a large number of drugs representing 49 therapeutic classes was designed to learn if cAMP-mediated reactions were the basis for the common mechanisms by which therapeutic agents act. The spectrum of tests included, in addition to action against PDE of the rat brain and cat heart, lipolysis in isolated fat cells of the rat, steroidogenesis in isolated rat adrenal cells, and effects on adenylate cyclase of guinea pig lung. The data indicated that cAMP-mediated reactions were not a common modality by which these classes of drugs acted. Activation and inhibition of adenylate cyclase were observed, but they occurred among the classes in no discernible pattern. A well-executed series of studies in Greengard's laboratory demonstrated the presence, in homogenates of caudate nucleus of rat brains, of a dopamine-stimulated adenylate cyclase. An important finding related to the stimulation of adenylate cyclase in the glial and neuronal cells of the brain was that the former may be stimulated by catecolamines and the latter by prostaclandins, especially by PGE1.

One hundred and fifty-eight compounds representing 49 classes of therapeutic agents were examined for their effects on steroidogenesis in isolated rat adrenal cells, on lipolysis in isolated rat lipocytes, on the activity of guinea pig lung adenylate cyclase, and on the activity of rat brain and cat heart cyclic nucleotide phosphodiesterase preparations. Classes of drugs active in the CNS appeared particularly active in the in vitro systems investigated, as did antiparasitic agents. Experience with general screening of compounds for effects on phosphodiesterase activity, along with data reported here, indicated a correlation between compounds with pharmacological activity in vivo and inhibition of phosphodiesterase activity in vitro. This is not to say that the pharmacological activities of the compounds necessarily arise from alterations of adenosine-3′,5′-monophosphate (cyclic AMP) metabolism.

Transactions of the New York Academy of SciencesVolume 30, Issue 6 Series II p. 794-803 SECTION OF BIOLOGICAL AND MEDICAL SCIENCES: THE EFFECT OF ACTIDIONE® AND ACTINOMYCIN D ON ANDROGEN-INDUCED BIOCHEMICAL CHANGES IN THE R3230AC MAMMARY CARCINOMA AND UTERUS OF THE RAT* Russell Hilf, Russell Hilf Squibb Institute for Medical Research, New Brunswick, N.J.Search for more papers by this authorLeonard J. Lerner, Leonard J. Lerner Squibb Institute for Medical Research, New Brunswick, N.J.Search for more papers by this authorDon N. Harris, Don N. Harris Squibb Institute for Medical Research, New Brunswick, N.J. With the technical assistance of Harold Goldenberg, Carlton Bell, and M. Joyce Carrington.Search for more papers by this author Russell Hilf, Russell Hilf Squibb Institute for Medical Research, New Brunswick, N.J.Search for more papers by this authorLeonard J. Lerner, Leonard J. Lerner Squibb Institute for Medical Research, New Brunswick, N.J.Search for more papers by this authorDon N. Harris, Don N. Harris Squibb Institute for Medical Research, New Brunswick, N.J. With the technical assistance of Harold Goldenberg, Carlton Bell, and M. Joyce Carrington.Search for more papers by this author First published: April 1968 https://doi.org/10.1111/j.2164-0947.1968.tb02523.xCitations: 3 † This paper was the third in a series of three papers on “Antagonism of Sex Hormone-Induced Changes in Selected Target Tissues in the Rat” presented at a meeting of the Section on March 11, 1968. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume30, Issue6 Series IIApril 1968Pages 794-803 RelatedInformation

Transactions of the New York Academy of SciencesVolume 30, Issue 6 Series II p. 783-793 SECTION OF BIOLOGICAL AND MEDICAL SCIENCES: THE EFFECT OF ANTAGONISTS ON ANDROGEN- AND ESTROGEN-INDUCED CHANGES IN THE MALE ACCESSORY SEX ORGANS OF THE RAT* Leonard J. Lerner, Leonard J. Lerner Squibb Institute for Medical Research, New Brunswick, N.J.Search for more papers by this authorRussell Hilf, Russell Hilf Squibb Institute for Medical Research, New Brunswick, N.J.Search for more papers by this authorDon N. Harris, Don N. Harris Squibb Institute for Medical Research, New Brunswick, N.J. With the technical assistance of A. Bianchi and I. Michel.Search for more papers by this author Leonard J. Lerner, Leonard J. Lerner Squibb Institute for Medical Research, New Brunswick, N.J.Search for more papers by this authorRussell Hilf, Russell Hilf Squibb Institute for Medical Research, New Brunswick, N.J.Search for more papers by this authorDon N. Harris, Don N. Harris Squibb Institute for Medical Research, New Brunswick, N.J. With the technical assistance of A. Bianchi and I. Michel.Search for more papers by this author First published: April 1968 https://doi.org/10.1111/j.2164-0947.1968.tb02522.xCitations: 12 † This paper was the second in a series of three papers on “Antagonism of Sex Hormone-Induced Changes in Selected Target Tissues in the Rat” presented at a meeting of the Section on March 11, 1968. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 Lerner, L. J., A. Bianchi & A. Borman. 1960. A-norprogesterone an androgen antagonist. Proc. Soc. Exp. Biol. Med. 103: 172. 2 Lerner, L. J., A. Bianchi & A. Borman. 1960. Anti-androgenic activity of A-norprogesterone in the intact male rats. Acta Endocrinol. Suppl. 51: 869. 3 Lerner, L. J., A. Bianchi & M. Dzelzkalns. 1963. A sensitive anti-androgen assay: Antagonism of locally applied androgen by A-norprogesterone inuncted on the chick comb. Acta Endocrinol. 44: 398. 4 Lerner, L. J. 1964. Hormone Antagonists: Inhibitors of specific activities of estrogen and androgen. Recent Progr. Hormone Res. 20: 435. 5 Lerner, L. J. 1958. Estrogen antagonistic activity of 1-(p-2-Diethylamino-ethoxyphenyl)-1-phenyl-2-p-anisylethanol (MER-25). Fed. Proc. 17: 388. 6 Lerner, L. J., F. J. Holthaus, Jr. & C. R. Thompson. 1958. A nonsteroidal estrogen antagonist 1-(p-2-Diethylaminoethoxyphenyl)-1-phenyl-2-p-ethoxyphenyl ethanol. Endocrinology 63: 295. 7 Lerner, L. J., R. Hilf, A. Bianchi & I. Michel. 1965. Antagonism of androgen and estrogen induced changes in accessory sex organs of the immature castrate male rat. Fed. Proc. 24: 638. 8 Schneider, W. C. 1945. Phosphorous compounds in animal tissues. I. Extraction and estimation of desoxypentose nucleic acid and of pentose nucleic acid. J. Biol. Chem. 214: 59. 9 Hilf, R., M. M. Johnson, C. Breuer, J. J. Freeman & A. Borman. 1963. Comparative biochemistry of three transplantable mammary tumors as influenced by steroid therapy. J. Nat. Cancer Inst. 31: 541. 10 Ceriotti, G. 1955. Determination of nucleic acids in animal tissues. J. Biol. Chem. 214: 59. 11 Dische, Z. 1955. Color reactions of nucleic acid compounds. In The Nucleic Acids: Chemistry and Biology. E. Chargoff & J. N. Davidson, eds. 1: 285. Academic Press, Inc., New York, N.Y.. 12 Glock, G. E. & P. McLean. 1953. Further studies on the properties and assay of glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase of rat liver. Biochem. J. 55: 400. 13 Ochoa, S., A. H. Mehler & A. Kornberg. 1948. Biosynthesis of dicarboxylic acids by carbon dioxide fixation. I. Isolation and properties of an enzyme from pigeon liver catalyzing the reversible oxidative decarboxylation of 1-malic acid. J. Biol. Chem. 174: 979. 14 Ochoa, S. 1948. Biosynthesis of tricarboxylic acids by carbon dioxide fixation. III. Enzymatic mechanisms. J. Biol. Chem. 174: 133. 15 Lerner, L. J., R. Hilf, A. R. Turkheimer, I. Michel & S. L. Engel. 1966. Effects of hormone antagonists on morphological and biochemical changes induced by hormonal steroids in the immature rat uterus. Endocrinology 78: 111. Citing Literature Volume30, Issue6 Series IIApril 1968Pages 783-793 ReferencesRelatedInformation

Transactions of the New York Academy of SciencesVolume 30, Issue 6 Series II p. 774-782 SECTION OF BIOLOGICAL AND MEDICAL SCIENCES: THE EFFECTS OF PROGESTERONE AND ETHAMOXYTRIPHETOL ON ESTRADIOL-INDUCED CHANGES IN THE IMMATURE RAT UTERUS* Don N. Harris, Don N. Harris Squibb Institute for Medical Research, New Brunswick, N.J.Search for more papers by this authorLeonard J. Lerner, Leonard J. Lerner Squibb Institute for Medical Research, New Brunswick, N.J.Search for more papers by this authorRussell Hilf, Russell Hilf Squibb Institute for Medical Research, New Brunswick, N.J. With the technical assistance of A. Bianchi, M. B. Phillips, and B. K. Raskin.Search for more papers by this author Don N. Harris, Don N. Harris Squibb Institute for Medical Research, New Brunswick, N.J.Search for more papers by this authorLeonard J. Lerner, Leonard J. Lerner Squibb Institute for Medical Research, New Brunswick, N.J.Search for more papers by this authorRussell Hilf, Russell Hilf Squibb Institute for Medical Research, New Brunswick, N.J. With the technical assistance of A. Bianchi, M. B. Phillips, and B. K. Raskin.Search for more papers by this author First published: April 1968 https://doi.org/10.1111/j.2164-0947.1968.tb02521.xCitations: 6 † This paper was the first in a series of three papers on “Antagonism of Sex Hormone-Induced Changes in Selected Target Tissues in the Rat” presented at a meeting of the Section on March 11, 1968. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 Mueller, G. C., J. Gorski & Y. Aizawa. 1961. The role of protein synthesis in early estrogen action. Proc. Nat. Acad. Sci. USA 47: 164–169. 2 UI, H. & G. C. Mueller. 1963. The role of RNA synthesis in early estrogen action. Proc. Nat. Acad. Sci. USA 50: 256–260. 3 Hamilton, T. H. 1963. Isotopic studies on estrogen-induced accelerations of ribonucleic acid and protein synthesis. Proc. Nat. Acad. Sci. USA 49: 373–379. 4 Means, A. R. & T. H. Hamilton. 1966. Early estrogen action: Concomitant stimulations within two minutes of nuclear RNA synthesis and uptake of RNA precursors by the uterus. Proc. Nat. Acad. Sci. USA 56: 1594–1598. 5 Hamilton, T. H., C. C. Widnell & J. R. Tata. 1968. Synthesis of ribonucleic acid during early estrogen action. J. Biol. Chem. 243: 408–417. 6 Aizawa, Y. & G. C. Mueller. 1961. The effect in viv and in vitro of estrogens on lipid synthesis in the rat uterus. J. Biol. Chem. 236: 381–386. 7 Gorski, J. & J. Nicolette. 1963. Early estrogen effects on newly synthesized RNA and phospholipid in subcellular fractions of rat uteri. Arch. Biochem. 103: 418–423. 8 Barker, K. L. & J. C. Warren. 1966. Estrogen control of carbohydrate metabolism in the rat uterus: Pathway of glucose metabolism. Endocrinology 78: 1205–1212. 9 Williams, H. E. & H. T. Provine. 1966. Effects of estradiol on glycogen synthetase in the rat uterus. Endocrinology 78: 786–790. 10 Velardo, J. T. 1959. Steroid hormones and uterine growth. Ann. N.Y. Acad. Sci. 75: 441–462. 11 Lerner, L. J., R. Hilf, R. Turkheimer, I. Michel & S. Engel. 1966. Effects of hormone antagonists on morphological and biochemical changes induced by hormonal steroids in the immature rat uterus. Endocrinology 78: 111–124. 12 Schneider, W. C. 1945. Phosphorus compounds in animals tissues. I. Extraction and estimation of desoxypentose nucleic acid and of pentose nucleic acid. J. Biol. Chem. 161: 293–303. 13 Cerriotti, G. 1955. Determination of nucleic acids in animal tissues. J. Biol. Chem. 214: 59–70. 14 Dische, Z. 1955. Color reactions of nucleic acid compounds. In The Nucleic Acids: Chemistry and Biology. E. Chargaff & J. N. Davidson, eds. 1: 285–305. Academic Press, Inc., New York, N.Y.. 15 Herranen, A. & G. C. Mueller. 1956. Effect of estradiol on the metabolism of serine-3-C14 in surviving uterine segments. J. Biol. Chem. 233: 369–375. 16 Hilf, R., I. Michel, G. Silverstein & C. Beli. 1965. Effect of actinomycin D on estrogen-induced changes in enzymes and nucleic acids of R3230AC mammary tumors, uteri and mammary glands. Cancer Res. 25: 1854–1859. 17 Mueller, G. C. 1964. The role of RNA and protein synthesis in estrogen action. Proc. Second Intern. Congr. Endocrinology 2: 19–29. 18 Singhal, R. L., J. R. E. Valadares & G. M. Ling. 1967. Estrogen-induced increase in phosphohexose isomerase activity in the rat uterus. Metabolism 16: 271–278. 19 Lerner, L. J. 1964. Hormone antagonists: Inhibitors of specific activities of estrogen and androgen. Recent Progr. Hormone Res. 20: 435–490. Citing Literature Volume30, Issue6 Series IIApril 1968Pages 774-782 ReferencesRelatedInformation