Prostaglandin Antagonists: Synthesis and Smooth Muscle Activity

Fried, Josef; Santhanakrishnan, T.S.; Himizu, Junichi; Lin, Cuikun; Ford, Susan; Rubin, Barry B.; Grigas, Eleanor O.

doi:10.1038/223208a0

Cited by 101 publications

(25 citation statements)

References 4 publications

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“…As seen in 7-oxa-13, 14-prostynoic acid, the replacement of C7 in PGE1 by an oxygen atom abolishes the vasodilator action, but it is not certain whether the absence of the vasodilator action in this compound is due to the alteration of the side chain alone, or of the cyclopentane ring. However, similar loss of the biological activities was also observed with 3-oxo-PGE, or 7-oxo-PGE, (Fried et al, 1969). Furthermore, the nonvascular smooth muscle-stimulating action of PGE1 is competitively antagonized by 7-oxa-13, 14-prostynoic acid, although no such inhibition was noticed with the vascular smooth muscles in the present study.…”

Section: Discussioncontrasting

confidence: 40%

“…Hence, it is rather difficult to assess the relationship between the structure of prostaglandins and their direct vasoactivities when one compares the depressor or pressor effect of different prostaglandins administered intravenously. Recently, as well as naturally occurring prostaglandins, several synthetic prostaglandin analogues have been synthesized by various investigators (Fried, Santhanak-ishnan, Himizu, Lin, Ford, Rubin & Grigas, 1969;Kloeze, 1969;Pike et al, 1967;Ramwell, Shaw, Corey & Andersen 1969 ;Lippman 1969). Although Kloeze (1969) studied the relationship between the structure and platelet aggregation activity of prostaglandins, no systematic study has been made on the relationships between the structure and direct vasoactivity of different prostaglandins.…”

Section: Introductionmentioning

confidence: 99%

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Relationship between the chemical structure of prostaglandins and their vasoactivities in dogs

Nakano

1972

British J Pharmacology

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Summary 1. The relationship between the chemical structure and the direct vasoactivity of different prostaglandins administered intra-arterially was studied in the dog hindlimb preparation.2. All of the prostaglandins studied, except PGFia and PGF2a, caused a dose related decrease in the femoral arterial perfusion pressure in dogs in which the femoral arterial blood flow was kept constant, indicating the direct vasodilator action of these prostaglandins. 3. Among the prostaglandins studied, PGE1 is the most potent vasodilator. Comparing the chemical structure and vasodilator action of PGE1 with those of different prostaglandins, the following conclusions can be made: 4. The formation of the A5 double bond in PGE1 causes no change in its vasodilator activity, whereas the saturation of the ,&" double bond of PGE1 slightly reduces its activity. 5. The alterations in the orientation and length of the carboxyl and alkyl side chains reduce markedly the vasodilator action of PGE-and PGA-compounds. 6. The presence of a carbonyl group at C9 is the most important requirement for the potent vasodilator action of PGE1. On the other hand, the presence and S-configuration of a hydroxyl group at C15 are essential for the intrinsic action at the receptor sites in the vascular smooth muscle, but may not be responsible for the vasodilator action. 7. The esterification of PGE1 or PGE2 and a triple bond formation and the replacement of C7 with oxygen in prostaglandin appear to reduce or abolish their vasodilator action.

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Section: Discussioncontrasting

confidence: 40%

Section: Introductionmentioning

confidence: 99%

Relationship between the chemical structure of prostaglandins and their vasoactivities in dogs

Nakano

1972

British J Pharmacology

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“…The experiments with compound 19396 are essentially an extension of the studies of Fried et al (1969) and those of Flack (1970). Some of the tissues used in our studies were different, and we studied PGE2 and PGF2a instead of PGE1.…”

Section: Discussionmentioning

confidence: 99%

“…Fried, Santhanakrishnan, Himizu, Lin, Ford, Rubin & Grigas (1969) synthesized several compounds, structurally related to the prostaglandins which had various degrees of antagonist activity against PGE1 on the longitudinal muscle of guinea-pig ileum, 'rabbit ileum and jird colon. The substance 7-oxa-13-prostynoic acid (compound 19396, Fig.…”

Section: Introductionmentioning

confidence: 99%

Studies on prostaglandin antagonists

Bennett

Posner

1971

British J Pharmacology

156

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Summary Three prostaglandin antagonists have been examined for their ability to block PGE2 and PGF2α on human, guinea‐pig and isolated rat gastrointestinal muscle. 7‐oxa‐13‐Prostynoic acid was either a non‐selective antagonist, or was ineffective on the tissues studied; it had marked spasmogenic activity on the rat fundus. 1‐Acetyl‐2‐(8‐chloro‐10,11‐dihydrodibenz (b,f)(1,4) oxazepine‐10‐carbonyl)hydrazine selectively antagonized the excitatory effects of PGE2 and PGF2α in guinea‐pig and rat tissues, but not in human muscle. Polyphloretin phosphate selectively antagonized the excitatory effects of prostaglandins in both human and guinea‐pig muscle preparations, but it caused stimulation of the rat fundus. All the antagonists lowered the tone in many tissues. They also reduced contractions caused by potassium. None of the compounds blocked the inhibitory effect of PGE2 on intestinal circular muscle. The implication of these results on the nature of prostaglandin receptors, and the value of each compound as a prostaglandin antagonist are discussed.

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“…Whatever the mode of interaction, it appears quite possible that prostaglandins may be the messengers modulating the behavior of activated intestinal adenylate cyclase. For this reason, we have examined the effects of prostaglandins and the lprostaglandin analogue, 7-oxa-13-prostynoic acid (PA) (11), on the adenylate cyclase activity of intestinal el)ithelial cells. Kinetic study was Tao and Lilpmann (12).…”

mentioning

confidence: 99%

Kinetic Evidence for the Presence of Two Postaglandin Receptor Sites Regulating the Activity of Intestinal Adenylate Cyclase Sensitive to Escherichia coli Enterotoxin

Kantor

Tao

Kiefer

1974

Proc. Natl. Acad. Sci. U.S.A.

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Kinetic behavior most consistent with the presence of two independent, but simultaneously acting, regulatory effector sites for prostaglandins has been presented for adenylate cyclase (EC 4.6.1.1) of rabbit intestinal epithelial cells. One site regulates activation of the catalytic site, while the other site regulates inhibition. A synthetic prostaglandin analogue, 7-oxa-13-prostynoic acid, is recognized at both sites in a concentration-dependent manner. At concentrations of 7-oxa-13-prostynoic acid less than 45 Ag/ml, activation is seen, while at higher concentrations, inhibition is seen. Different naturally occurring prostaglandins appear to be site-specific. Prostaglandin El gives only activation of the cyclase, while prostaglandin Al gives only inhibition of the activated cyclase. When saturating concentrations of prostaglandin E, are used to activate adenylate cyclase, no further activation by 7-oxa-13-prostynoic acid can be elicited, indicating that both molecules activate at the same site. The similarity of inhibition constants for both 7-oxa-13-prostynoic acid and prostaglandin A, suggests that the mode of binding is the same for both compounds and that they probably inhibit by acting at the same site. The inhibition by 7-oxa-13-prostynoic acid and by prostaglandin Al overrides enzyme activation produced by either Escherichia coli enterotoxin, prostaglandin El, or sodium fluoride, suggesting that in intestinal adenylate cyclase this site is the primary regulatory site (i.e., primary allosteric effector site) for enzyme activity. These data suggest that sites exist on adenylate cyclase which would allow prostaglandins to serve as the intracellular messengers by which the cell controls its adenylate-cyclase-mediated response to extracellular stimulation, as with hormones.

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Prostaglandin Antagonists: Synthesis and Smooth Muscle Activity

Cited by 101 publications

References 4 publications

Relationship between the chemical structure of prostaglandins and their vasoactivities in dogs

Relationship between the chemical structure of prostaglandins and their vasoactivities in dogs

Studies on prostaglandin antagonists

Kinetic Evidence for the Presence of Two Postaglandin Receptor Sites Regulating the Activity of Intestinal Adenylate Cyclase Sensitive to Escherichia coli Enterotoxin

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