Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01178 (oxytocin)
 15,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since oxytocin agonists and antagonists have different structure-activity relationships, we have investigated the stereostructural and stereoelectronic requirements of the Asn5 residue in oxytocin antagonists by the synthesis of four analogues of the potent, prolonged acting oxytocin antagonist [Pen1,D-Phe2,Thr4,Orn8]-oxytocin (I) in which Asn5 was replaced respectively with Thr (II), Leu5 (III), Asp5 (IV) and Tyr5 (V). These analogues had pA2 values in the antioxytocic in vitro rat uterine assay of 7.23 (I), 7.16 (II), 6.67 (III), 7.21 (IV), and 6.76 (IV), respectively. All were also found to be weakly potent in the in vivo anti-vasopressor assay in the rat. These studies demonstrate very different structural and stereoelectronic requirements for oxytocin agonists and antagonists when they interact with the oxytocin uterine receptor.
 ...
PMID:Oxytocin antagonists with changes in the Asn5 position shed light on hormone-oxytocin receptor interactions. 165 4

We discovered an enzyme in human platelets that deamidates substance P and other tachykinins. Because an amidated carboxyl terminus is important for biological activity, we purified and characterized this deamidase. The enzyme, released from human platelets by thrombin, was purified to homogeneity by ammonium sulfate precipitation, followed by chromatography on an octyl-Sepharose column and chromatofocusing on PBE 94. The purified enzyme exhibits esterase, peptidase, and deamidase activities. The peptidase activity (with furylacryloyl-Phe-Phe) is optimal at pH 5.0 while the esterase (benzoyl-tyrosine ethyl ester) and deamidase (D-Ala2-Leu5-enkephalinamide) activities are optimal at pH 7.0. With biologically important peptides, the enzyme acts both as a deamidase (substance P, neurokinin A, and eledoisin) and a carboxy-peptidase (with bradykinin, angiotensin I, substance P-free acid, oxytocin-free acid) at neutrality, although the carboxypeptidase action is faster at pH 5.5. Enkephalins, released upon deamidation of enkephalinamides, were not cleaved. Gly9-NH2 of oxytocin was released without deamidation. Peptides with a penultimate Arg residue were not hydrolyzed. Some properties of the deamidase are similar to those reported for cathepsin A. The deamidase is inhibited by diisopropylfluorophosphate, inhibitors of chymotrypsin-type enzymes, and mercury compounds while other inhibitors of catheptic enzymes, trypsin-like enzymes, and metalloproteases were ineffective. In gel filtration, the native enzyme has an Mr = 94,000 while in non-reducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis the Mr = 52,000 indicating it exists as a dimer. After reduction, deamidase dissociates into two chains of Mr = 33,000 and 21,000 as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. [3H]diisopropylfluorophosphate labeled the active site serine in the Mr = 33,000 chain. The first 25 amino acids of both chains were sequenced. They are identical with the sequences of the two chains of lysosomal "protective protein" which, in turn, has sequence similarity to the KEX1 gene product and carboxypeptidase Y of yeast. This protective protein complexes with beta-galactosidase and neuraminidase in lysosomes and is vitally important in maintaining their activity and stability. A defect in this protein is the cause of galactosialidosis, a severe genetic disorder. The ability of physiological stimuli (e.g. thrombin or collagen) to release the deamidase from platelets indicates that it may also be involved in the local metabolism of bioactive peptides.
 ...
PMID:A peptidase in human platelets that deamidates tachykinins. Probable identity with the lysosomal "protective protein". 169 76

The rat neurohypophysis contains both opioid receptors and substantial amounts of endogenous opioid peptides. Inhibitory influences of opioids on the secretion of both oxytocin and vasopressin have been described. We have examined the effects of a range of opioid agonists and antagonists with differing relative selectivities towards opioid receptor subclasses on the secretion of oxytocin and vasopressin from the isolated neurohypophysis. Oxytocin and vasopressin release evoked by brief periods of electrical stimulation in control experiments was compared to evoked release in the presence of test compounds. Oxytocin release was depressed approximately 25% by the delta-agonist (D-Ala2, D-Leu5)-enkephalin but not affected by putative kappa-agonists or by beta-endorphin. The use of opioid antagonists revealed a strong inhibition of oxytocin secretion by endogenous opioids released during electrical stimulation. Naloxone, relatively mu-selective, enhanced oxytocin secretion by up to 90% with a half-maximal effect at approximately 10(-6) M. MR2266, a relatively kappa-selective antagonist also enhanced oxytocin secretion but displayed agonist-like activity at high concentrations. ICI 154129, a delta-selective antagonist, was without effect on oxytocin secretion. Vasopressin release was unaffected by any of the agonists tested and not potentiated by antagonists at a range of stimulation frequencies. The data do not support the suggestion of an inhibitory endogenous opioid influence over vasopressin secretion within the neurohypophysis but indicate that an endogenous opioid peptide, possibly acting via mu- or kappa rather than delta-receptors, strongly suppresses the secretion of oxytocin.
 ...
PMID:Effects of opioid agonists and antagonists on oxytocin and vasopressin release in vitro. 286 49

Rat neurointermediate lobes and neurohypophyses separated from the pars intermedia were stimulated in vitro in the presence of either D-Ala2, D-Leu5-enkephalin (DADLE), a Leu-enkephalin stable analogue or FK 33-824 a Met-enkephalin stable analogue. Secretion of vasopressin (AVP) and oxytocin (OT) was produced by either a Ca2+-ionophore or with electrical stimulation or by K+-induced depolarization. These opioid peptides and their antagonist naloxone did not affect basal nor evoked hormone release. Furthermore, they did not affect the evoked calcium uptake induced with electrical stimulation. These findings were confirmed using a preparation of isolated neurosecretory nerve endings. Further, dopamine had no effect on the K+-induced AVP release although a crude extract of the pars intermedia abolished the electrically-evoked and reduced considerably the potassium-evoked AVP release. It is concluded that in the neurohypophysis neither Leu- and Met-enkephalin nor dopamine affect the secretion-coupling mechanism at the level of the neurosecretory nerve endings.
 ...
PMID:Do opioid peptides modulate, at the level of the nerve endings, the release of neurohypophysial hormones? 351 53

The effects on oxytocin release of enkephalin analogues, thought to be highly selective agonists of the mu or delta opioid receptor, were compared. Oxytocin release was evoked in urethane-anaesthetised rats (7-10 days post partum) by intracerebroventricular injection of NaCl (3M) at 15-20 min. intervals and detected by the resultant increase in intramammary pressure. Enkephalin analogues (the mu receptor agonist Tyr-D-Ala-Gly-MePhe-NH (CH2)2OH (DAGO), the delta receptor agonist (D-Ala2-D-Leu5) - enkephalin (DADLE) and metkephamid, which has been reported to be particularly efficacious at the delta receptor) were administered intracerebroventricularly 3-5 min. prior to hypertonic saline. Oxytocin release was inhibited in a dose-dependent, naloxone-reversable manner by DAGO (ED50 : 40ng), DADLE (ED50 : 156ng) and metkephamid (ED50 : 42ng); the mammary gland sensitivity to oxytocin was unaffected. These results suggest that the inhibitory action may be mediated through both mu and delta receptors and provide further evidence in support of a role of enkephalins in the control of oxytocin secretion.
 ...
PMID:Inhibition of oxytocin secretion by mu and delta receptor selective enkephalin analogues. 609 11

Experiments were performed to investigate the effects of morphine and [D-Ala2, D-Leu5]enkephalin on supraoptic cells in hypothalamic slices in vitro. To ensure the presence of a steady background activity, the cells were recorded with glutamate-filled glass microelectrodes and the level of activity was controlled by selecting a suitable retaining current (0.1-9.8 nA). Under these conditions, supraoptic cells showed either the non-phasic (65%) or phasic (35%) firing pattern previously associated with oxytocin or vasopressin cells, respectively. During perifusion of the slice with morphine (10 microM), 10 out of 17 non-phasic supraoptic cells were profoundly inhibited, five cells showed no response and the remaining 2 cells were excited. Similarly with [D-Ala2, D-Leu5]enkephalin (10 microM), 11 out of 15 non-phasic cells were inhibited, 3 cells showed no response and 1 cell was excited. The inhibition produced by morphine or [D-Ala2, D-Leu5]enkephalin could be reversed by concomitant application of naloxone (10 microM). In contrast to the profound effects seen in the non-phasic cells, only 1 out of 13 phasic cells tested with either morphine or [D-Ala2, D-Leu5]enkephalin was inhibited. The remaining 12 phasic cells showed no change in either their overall firing rate or pattern of activity during opiate perifusion. These results provide further evidence that, in addition to their inhibitory effects within the posterior pituitary, opiates can directly suppress the electrical activity of magnocellular neurosecretory cells at the level of the hypothalamus. However, the absence of an opiate effect on the phasic cells might suggest that the action of opioid peptides within the hypothalamus would be exerted predominantly on the oxytocin, rather than the vasopressin cells.
 ...
PMID:Effects of morphine and D-Ala, D-Leu enkephalin on the electrical activity of supraoptic neurosecretory cells in vitro. 635 43