cis- and trans-2-Mercaptocyclobutylamines, their benzylmercapto analogs, and aminomethyl homologs. Influence on bradykinin-induced contraction of the guinea pig ileum

Abstract

Many thio compounds, including 2-mercaptoethylamine ( l ) , have been shown to potentiate the effect of bradykinin on smooth muscle. In this paper we describe the synthesis of cyclic analogs, cis-and trans-2-mercaptocyclobutylmethylamine (3), and the action of these stereoisomers as well as cisand trans-2-mercaptocyclobutylamine (2) and cis-and trans-2-benzylmercaptocyclobutylamine (4) on bradykinin-induced contraction of the guinea pig ileum. Biological results are discussed in light of current proposals concerning the mechanism of action of thio analog influence on bradykinin contraction of the guinea pig ileum.The action of bradykinin on smooth muscle is of considerable importance; this polypeptide is a potent stimulator of many smooth muscles including guinea pig ileum, rabbit intestine, and rat uterus, exhibits a relaxant action on the rat duodenum and colon, and produces a fall in blood pressure in a number of small animals.' In addition, a number of SH compounds, such as 2-mercaptoethylamine (l), glutathione, cysteine, 2,3-dimercaptopropanol, and 2-mercaptoethanol, are known to potentiate bradykinin-induced contraction of the guinea pig i l e~m .~-~ Since Potter and Walaszek6j7 concluded that the NH2 and SH groups of cysteine are essential for the potentiating action of this amino acid, it seemed desirable to us to study the stereoselective effects of some recently synthesized' cyclobutane analogs of 1 in this system. Appropriately constructed compounds ultimately may serve as probes useful in elucidating structural requirements and mechanisms involved in bradykinin-induced responses of smooth muscle.The comparative effects of cis-and trans-2-mercaptocyclobutylamine (2), the aminomethyl homologs (cis-and trans-3), and the benzyl thioethers (cis-and trans-4) on bradykinininduced contraction of the guinea pig ileum are described in this article. / "2 d R +R --SR' U I S H SR' 1 cis-2, R = NH,; R' = H cis-3, R = CH,NH,; R' = H cis-4, R = NH,; R = CH,Ph trans-2, R = NH, ; R' = H trans-3, R = CH,NH,; R' = H trans-4, R = NH,; R' = CH,PhSynthetic Aspects. The synthesis for cis-and trans-2 and the isomerically pure benzyl thioethers 4 previously have been described.8 The isomeric homologs of 2, namely 3, were prepared from starting cis-or trans-2-benzylmercapto-1 -carbethoxycyclobutane (5).' LiAlH4 reduction of pure cis-or trans-5 afforded the respective cis-or trans-2-benzylmercaptocyclobutylcarbinols (6) in 85-90% yield. The cistosylate 7 was obtained from carbinol 6 as a crystalline solid; the trans-tosylate 7 could not be crystallized. The latter isomer was purified by dissolving in a minimum amount of HCC13 followed by precipitation with a large ?The authors gratefully acknowledge support of this work through Contract N o . $This work as well as ref 8 was abstracted in part from a dissertation presented b y B. K. S., March 1972, t o the Graduate School o f The Ohio State University.volume of petroleum ether. Treatment of cis-or trans-7 with a 10 M excess of NaN3 in dry DMF afforded the respective cis-azide (N3...

Study of trans-cyclopropylbis(diketopiperazine) and chelating agents related to ICRF 159. Cytotoxicity, mutagenicity, and effects on scheduled and unscheduled DNA synthesis

“…Dose-survival curves for V-79A in the presence of various concentrations of analogues: 1, X-X-X; 3, A-A-A; 6, --; Mutagenicity.42 Table I summarizes the frequency of formation of cell variants in culture resistant to a concentration of 1.0 mM ouabain. Each analogue was tested at three concentrations for 24 [3H]Thymidine concentration equals 0.1 mCí/hiL (sp act. = 5 Ci/mM) in modified MEM(E) + 10% FBS.…”