Structure-desensitization relationships of angiotensin analogues in the rat isolated uterus.

The desensitizing potencies of angiotensin II (ANG II) analogues modified at positions 1, 2, 4, 7, and 8 have been examined in the rat isolated uterus assay by determining the time of recovery of the half-maximal concentration (EC50) response to angiotensin II after treatment of the tissues with a high dose (10(-5) M) of each analogue for 2 min. The magnitude of the desensitization effect was substituent dependent in the following manner: position 1, sarcosine (Sar) greater than Asp greater than des-Asp; position 2, Arg greater than Sar; position 4, Tyr greater than Tyr(Me) approximately Phe; position 7, 3,4-dehydroproline (Dpr) greater than Pro greater than thioproline (Tpr) greater than Sar; position 8, Ile greater than D-Trp greater than Ala greater than Phe. The "additivity" rule applied to these structure-desensitization relationships and the most potent desensitizer, requiring 3 h for reestablishment of the EC50 response, was [Sar1, Dpr7, Ile8]-ANG II. The desensitizing potencies of these analogues did not correlate with agonist or antagonist activities and demonstrated that the angiotensin-mediated tissue desensitization process has unique structural determinants. Methylation or elimination of the tyrosine hydroxyl group of strong desensitizers virtually eliminated the desensitization effect, implicating the phenoxyl moiety in the mechanism of desensitization. The initial phase of recovery of angiotensin responsiveness after desensitization by several analogues appeared to obey first-order kinetics. The results are discussed in the contexts of both one- and two-site receptor models.

Synthesis of angiotensin II antagonists containing sarcosine in position 7.

Analogues of the type [1-sarcosine,7-sarcosine, 8-X]angiotensin II, where X = isoleucine, leucine, alanine, methionine, O-methylthreonine, or DL-alloisoleucine, were synthesized by the solid-phase method and purified by partition chromatography, cation-exchange chromatography, and high-pressure liquid chromatography. In the isolated rat uterus, these analogues had activities of less than 0.1, less than 0.1, less than 0.1, less than 0.1, less than 0.1, and 0.7%, respectively, of the hyotropic activity of angiotensin II and inhibited the contractile response to angiotensin II with pA2 values of 8.1, 7.2, 6.7, 7.7, 7.4, and 8.4, respectively. In the vagotomized ganglion blocked rat, the analogues had 0.7, 0.21, 0.06, 0.72, 0.13, and 12.5%, respectively, of the pressor activity of angiotensin II.