Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01185 (vasopressin)
 23,126 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report the solid-phase synthesis and some pharmacological properties of 12 position three modified analogues (peptides 1-12) of the potent non-selective antagonist of the antidiuretic (V2-receptor), vasopressor (V1a-receptor) responses to arginine vasopressin (AVP) and of the uterine contracting (OT-receptor) responses to oxytocin (OT), [1(-beta mercapto-beta,beta-pentamethylenepropionic acid)-2-O-ethyl-D-tyrosine 4-valine] arginine vasopressin [d(CH2)5D-Tyr(Et)2VAVP] (A) and two analogues of (B) (peptides 13,14), the 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid3 (Tic3) analogue of (A). Peptides 1-12 have the following substituents at position three in (A): (1) Pro; (2) Oic; (3) Atc; (4) D-Atc; (6) D-Phe; (7) Ile; (8) Leu; (9) Tyr; (10) Trp; (11) Hphe; (12) [HO]Tic; Peptide (13) is the Tyr-NH2(9) analogue of (B): Peptide (14) is the D-Cys(6) analogue of (B). All 14 new peptides were evaluated for agonistic and antagonistic activities in in vivo V2 and V1a assays and in vitro (no Mg2+)n oxytocic assays. With the exception of the D-Phe3 peptide (No. 6), which exhibits very weak V2 agonism (approximately 0.0017 U/mg), none of the remaining 13 peptides exhibit any agonistic activities in these assays. In striking contrast to their deleterious effects on agonistic activities in AVP, the Pro3, Oic3, Tyr3 and Hphe3 substitutions in (A) are very well tolerated, leading to excellent retention of V2, V1a and OT antagonistic potencies. All are more potent as V2 antagonists than the Ile3 and Leu3 analogues of (A). The Tyr-NH2(9) and D-Cys(6) substitutions in (B) are also well tolerated. The anti-V2 pA2 values of peptides 1-5 and 7-14 are as follows (1) 7.77 +/- 0.03; (2) 7.41 +/- 0.05; (3) 6.86 +/- 0.02; (4) 5.66 +/- 0.09; (5) approximately 5.2; (7) 7.25 +/- 0.08; (8) 6.82 +/- 0.06; (9) 7.58 +/- 0.05; (10) 7.61 +/- 0.08; (11) 7.59 +/- 0.07; (12) 7.20 +/- 0.05; (13) 7.57 +/- 0.1; (14) 7.52 +/- 0.06. All analogues antagonize the vasopressor responses to AVP, with anti-V1a pA2 values ranging from 5.62 to 7.64, and the in vitro responses to OT, with anti-OT pA2 values ranging from 5.79 to 7.94. With an anti-V2 potency of 7.77 +/- 0.03, the Pro3 analogue of (A) is surprisingly equipotent with (A), (anti-V2 pA2 = 7.81 +/- 0.07). These findings clearly indicate that position three in AVP V2/V1a antagonists, in contrast to position three in AVP agonists, is much more amenable to structural modification than had heretofore been anticipated. Furthermore, the surprising retention of V2 antagonism exhibited by the Pro3, Oic3, Tyr3, Trp3 and Hphe3 analogues of (A), together with the excellent retention of V2 antagonism by the Tyr-NH2(9) and D-Cys6 analogues of (B) are promising new leads to the design of potent and possibly orally active V2 antagonists for use as pharmacological tools and/or as radioiodinatable ligands and for development as potential therapeutic agents for the treatment of the hyponatremia caused by the syndrome of the inappropriate secretion of the antidiuretic hormone (SIADH).
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PMID:Position three in vasopressin antagonist tolerates conformationally restricted and aromatic amino acid substitutions: a striking contrast with vasopressin agonists. 923 Apr 69

Effects of different psychological stimuli on oxytocin (OT) and vasopressin (AVP) secretion are reviewed in animals and in humans. The secretion of neuropituitary hormones is also discussed in various psychiatric diseases such an anorexia nervosa, bipolar disorder, schizophrenia and obsessive-compulsive disorder. AVP and OT are secreted into the hypophyseal portal circulation by neurons which project from the paraventricular nucleus to the external zone of the median eminence. AVP and OT-containing neurons in the suprachiasmatic and paraventricular nuclei project to limbic areas, including the hippocampus, the subiculum, the ventral nucleus of the amygdala and the nucleus of the diagonal band. Specific AVP receptors which are pharmacologically different from the pressor and antidiuretic AVP receptors have been found in the anterior pituitary. OT receptors have been identified in a variety of forebrain sites. The neurohypophyseal secretion is regulated by the cholinergic muscarinic, histaminergic and beta-adrenergic systems. Stress alters the secretion of one or more of the hypothalamic factors which interact at the pituitary to increase the secretion of ACTH. AVP and OT have been shown to modulate the effect of Corticotropin-Releasing Factor (CRF) on ACTH secretion and appear to play a key role in mediating the ACTH response to stress. Although AVP is a relatively weak secretagogue for ACTH, it markedly potentiates the activity of CRF both in vitro and in vivo. The role of OT is more complex. In vitro, OT stimulates ACTH release at high doses whereas in human it inhibits ACTH secretion at low doses. The type of stressor appear to determine the relative importance of these secretatogues in ACTH response. Several recent studies indicate that psychological stressors display a similar degree of variety of secretagogue release patterns as was found earlier for physical stressors. A bewildering array of technique produces a bewildering array of conclusions. In rats, OT may be an important secretagogue during a novel stimulus, whereas the role for AVP is less clear. Indeed two studies out of ten suggest a stimulating role for AVP. In response to frustration and submission, OT and AVP are secreted. Regarding social isolation, results are difficult to interpret and the role of AVP could be species-dependent. In contrast plasma OT levels do not change. After restraint, ACTH release is primarily mediated by the active increase of OT and AVP does not appear to play a role. When restraint is associated with moderate levels of physical components and during immobilisation, all two secretagogs are involved in the ACTH response. With fear, ACTH response appears to be driven by OT. In humans, one study indicates that high emotionality women increase plasma OT in response to uncontrollable noise. Various neuroendocrine dysregulations have been observed in psychiatric disease. Either an increase or a decrease of the hypothalamic-pituitary-adrenal (HPA) function have been described in several illnesses. Effects of OT appear to be reciprocal to the effects of AVP. OT has been called the "amnestic" neuropeptide due to its capacity to attenuate memory consolidation and retrieval. AVP exhibits a central activating action on mood, memory and selective attention. Underweight patients with anorexia nervosa have abnormally high levels of centrally directed AVP and reduced OT levels. These modifications could enhance the retention of cognitive distortions of aversive consequences of eating. Patients with bipolar disorder show a biphasic secretion of AVP. Depressive episodes are associated with decreased vasopressinergic activity whereas manic episodes involve an increased release. AVP might be responsible for an increased catecholamine activity. In addition, lithium could act as an antagonist to AVP. In schizophrenic patients, studies using the apomorphine stimulation suggest increased oxytoninergic and decreased vasopressinergic functions. These findings are consistent with the beneficial role of AVP on schizophrenic symptoms noted in several trials. The increased OT could be responsible for "positive" symptomatology such as delusions and hallucinations. Obsessive compulsive disorder (OCD) includes a range of cognitive and behavioral disturbances that could be influenced by OT. In animals, several studies have emphasized the role of AVP in promoting repetitive grooming behaviors and maintaining conditioned response to aversive stimuli. In OCD patients, one study have reported that AVP/OT ratio was negatively correlated with symptom severity. However, an independent report found similar AVP concentrations in OC patients without a personal or family history of tic disorder and in normal subjects. Whether these modifications are only a consequence of the central disturbances or whether those peptides could participate in the pathogenesis of these affections remains to be elucidated.
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PMID:[Role of the neurohypophysis in psychological stress]. 1148 55