INVESTIGATION OF NATRIURETIC, ANTIDIURETIC AND OXYTOCIC ACTIONS OF NEUROHYPOPHYSEAL HORMONES AND RELATED PEPTIDES - DELINEATION OF SEPARATE MECHANISMS OF ACTION AND ASSESSMENT OF MOLECULAR REQUIREMENTS

Abstract

The substitution of the 4-glutamine of oxytocin by a lipophilic aliphatic amino acid leucine yields [4-Leu]oxytocin which possesses natriuretic-diuretic anti-arginine-vasopressin (anti-ADH) activities. Alkyl substitutions of the .beta.-carbon of the 1/2-cystine of oxytocin yield a series of antioxytocin analogs which inhibit the uterotonic response to oxytocin. The results of further investigations on the molecular requirements for natriuretic, anti-ADH and antioxytocic activities of these peptides are reported. A total of 12 analogs of oxytocin and lysine-vasopressin (LVP) with leucine and/or .beta.-carbon alkyl substitutions were studied. The effect of 4-leucine substitution may not be to enhance the natriuretic activity but rather to abolish the antidiuretic activity of oxytocin. The lack of antidiuretic activity of these 4-leucine analogs makes it possible to unmask the intrinsic natriuretic activity of these peptides at the high dose level. Structure-activity correlations suggest that the oxytocin molecule may be the optimal requirement for natriuretic activity of these peptides. Substitution of 4-glutamine by lipophilic aromatic phenylalanine yields [4-Phe]oxytocin which possesses anti-ADH activity with little or no natriuretic activity. The hybrid antioxytocin and anti-ADH molecules, .beta.-carbon alkyl and 4-leucine substituted analogs did not possess enhanced antihormone activity. Although they had antioxytocic and antipressor activities, they were less potent than their respective singly alkyl substituted analogs. They had no demonstrable anti-ADH activity. The singly alkyl substituted oxytocin and LVP also had no anti-ADH activity. .beta.-carbon alkyl substitution had different effects on activities depending on the morphological features and the functions of the target cell. In target cells of contractile smooth muscles (uterus and vascular), the alkyl substituted analogs had no intrinsic activity but retained a relatively high receptor affinity to become effective antagonists to the natural hormone. In target cells of the renal tubule which are noncontractile epithelial cells, both intrinsic activity and receptor affinity were reduced or abolished. None of these alkyl substituted analogs possessed more than very slight antidiuretic activity, and none had any natriuretic or anti-ADH activity.