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

Pharmacological studies in humans and animals suggest the existence of vascular endothelial vasopressin (AVP)/oxytocin (OT) receptors that mediate a vasodilatory effect. However, the nature of the receptor subtype(s) involved in this vasodilatory response remains controversial, and its coupled intracellular pathways are unknown. Thus, we set out to determine the type and signaling pathways of the AVP/OT receptor(s) expressed in human vascular endothelial cells (ECs). Saturation binding experiments with purified membranes of primary cultures of ECs from human umbilical vein (HUVEC), aorta (HAEC), and pulmonary artery (HPAEC) and [3H]AVP or [3H]OT revealed the existence of specific binding sites with a greater affinity for OT than AVP (Kd = 1.75 vs. 16.58 nM). Competition binding experiments in intact HUVECs (ECV304 cell line) with the AVP antagonist [125I]4-hydroxyphenacetyl-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-NH2 or the OT antagonist [125I]D(CH2)5[O-Me-Tyr-Thr-Orn-Tyr-NH2]vasotocin, and various AVP/OT analogs confirmed the existence of a single class of surface receptors of the classical OT subtype. RT-PCR experiments with total RNA extracted from HUVEC, HAEC, and HPAEC and specific primers for the human V1 vascular, V2 renal, V3 pituitary, and OT receptors amplified the OT receptor sequence only. No new receptor subtype could be amplified when using degenerate primers. DNA sequencing of the coding region of the human EC OT receptor revealed a nucleotide sequence 100% homologous to that of the uterine OT receptor reported previously. Stimulation of ECs by OT produced mobilization of intracellular calcium and the release of nitric oxide that was prevented by chelation of extra- and intracellular calcium. No stimulation of cAMP or PG production was noted. Finally, OT stimulation of ECs led to a calcium- and protein kinase C-dependent cellular proliferation response. Thus, human vascular ECs express OT receptors that are structurally identical to the uterine and mammary OT receptors. These endothelial OT receptors produce a calcium-dependent vasodilatory response via stimulation of the nitric oxide pathway and have a trophic action.
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PMID:Human vascular endothelial cells express oxytocin receptors. 1006 57

Most bony vertebrate species display a great evolutionary stability of their two neurohypophysial hormones, so that two molecular lineages, isotocin-mesotocin-oxytocin and vasotocin-vasopressin, have been traced from bony fishes to mammals. Chondrichthyes, in contrast, show a striking diversity of their oxytocin-like hormones, yet show a substantial decrease in vasotocin stored in neurohypophysis when compared to nonmammalian bony vertebrates. In the rays, glumitocin ([Ser(4),Gln(8)]-oxytocin) has been identified. In the spiny dogfish, aspargtocin ([Asn4]-oxytocin) and valitocin ([Val(8)]-oxytocin) have been characterized whereas in the spotted dogfish, asvatocin ([Asn(4),Val(8)]-oxytocin) and phasvatocin ([Phe(3),Asn(4),Val(8)]-oxytocin) have been found. Finally, in the holocephalian Pacific ratfish, oxytocin, the typical peptide of placental mammals, has been discovered. The duplication of the oxytocin-like hormone gene found in dogfishes has been observed only in some Australian and American marsupials. Cartilaginous fishes have developed an original urea-based osmoregulation involving a glutamine-dependent urea synthesis and blood urea retention through renal urea transporters. Furthermore, marine species use a rectal salt gland for sodium chloride excretion. Although vasopressin, in mammals, and vasotocin, in nonmammalian tetrapods, are clearly implied in water and salt homeostasis, the hormones involved in the blood osmotic pressure regulation of elasmobranchs are still largely unknown. It is suggested that the great diversity of oxytocin-like hormones in elasmobranchs expresses a release from an evolutionary receptor-binding constraint, so that amino-acid substitutions reflect neutral evolution. In contrast, the preservation of vasotocin suggests a selective pressure, which may be related to the regulation of renal urea transporter-recruitment mechanisms, as it has been shown for vasopressin in mammals. J. Exp. Zool. 284:475-484, 1999.
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PMID:Unique evolution of neurohypophysial hormones in cartilaginous fishes: possible implications for urea-based osmoregulation. 1046 84

Using a segment strategy, we have synthesized four iodinated photoactivatable cyclic peptidic ligands of oxytocin, bearing a beta-mercapto-betabeta-cyclopentamethylene propionic group (Pmp) on their N-terminus. All the syntheses were RP-HPLC monitored, and the compounds were HPLC purified. They were characterized by 1H NMR, MALDI-TOF, or FAB mass spectrometries. The affinities of Pmp-Tyr(Me)-Ile-Thr-Asn-Cys-Gly-Orn-Phe(3I,4N3)-NH2 (20), Pmp-Tyr-Ile-Thr-Asn-Cys-Gly-Orn-Phe(3I,4N3)-NH2 (21), Pmp-Tyr(Me)-Ile-Thr-Asn-Cys-Pro-Orn-Phe(3I,4N3)-NH2 (22), and Pmp-Tyr-Ile-Thr-Asn-Cys-Pro-Orn-Phe(3I,4N3)-NH2 (23) were evaluated as inhibition constants (K(i), in nM) for the human oxytocin receptor expressed in Chinese hamster ovary cells by displacement of a radioiodinated disulfide-cyclized antagonist (Elands et al. Eur. J. Pharmacol. 1987, 147, 197-207). The most potent of them, compound 22, was synthesized by another method in order to allow its radiolabeling by 125I. Its dissociation constant (K(d)) for the human oxytocin receptor, directly measured in saturation studies, was 0.25 +/- 0.04 nM, and its antagonist properties were determined by inactivation of phospholipase C, thus obtaining an inactivation constant (K(inact)) of 0.18 +/- 0.02 nM, evaluated by inositol phosphate accumulation. This compound is a very good tool for the mapping of peptidic antagonist binding sites in the human oxytocin receptor.
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PMID:Design, synthesis and pharmacological characterization of a potent radioiodinated and photoactivatable peptidic oxytocin antagonist. 1152 Feb 11

Oxytocin is a neurohypophyseal peptide hormone that induces labor and lactation in mammals. An inverse gamma-turn mimetic corresponding to the tripeptide Ile-Val-Asn has been synthesized and incorporated instead of residues 3-5 of oxytocin to probe the hypothesis that a gamma-turn involving these residues is found in the receptor bound conformation of oxytocin. In the turn mimetic, residues i and i + 1 are connected by a psi[CH(2)O] isostere while a covalent methylene bridge replaces the hydrogen bond that is often found between residues i and i + 2 in gamma-turns. The turn mimetic was assembled from three types of building blocks: an azido epoxide, an alpha-bromo acid, and a protected beta-amino alcohol. The oxytocin analogue did not induce contractions of the uterus nor did it inhibit oxytocin-induced contractions. It is suggested that the loss of bioactivity is mainly due to the presence of a psi[CH(2)O] isostere instead of an amide bond between residues i and i + 1 in the turn mimetic.
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PMID:Synthesis and pharmacological evaluation of an analogue of the peptide hormone oxytocin that contains a mimetic of an inverse gamma-turn. 1203 59

The glutamine(4) residue in [deamino-Cys(1)]arginine vasopressin (dAVP) was replaced by a broad series of aliphatic, aromatic, polar, and charged amino acids to give the following peptides: d[Gly(4)]AVP (1), d[Ala(4)]AVP (2), d[Abu(4)]AVP (3), d[Nva(4)]AVP (4), d[Nle(4)]AVP (5), d[Leu(4)]AVP (6), d[Ile(4)]AVP (7), d[Thi(4)]AVP (8), d[Phe(4)]AVP (9), d[Tyr(4)]AVP (10), d[Trp(4)]AVP (11), d[Asn(4)]AVP (12), d[Ser(4)]AVP (13), d[Thr(4)]AVP (14), d[Dap(4)]AVP (15), d[Dab(4)]AVP (16), d[Orn(4)]AVP (17), d[Lys(4)]AVP (18), d[Arg(4)]AVP (19), d[Har(4)]AVP (20), and d[Glu(4)]AVP (21). All peptides were synthesized by solid-phase methods using BOC chemistry for all but one peptide (8), which required the use of Fmoc chemistry. The binding and functional properties of these position 4 substituted analogues of dAVP (d[X(4)]AVP) and the previously reported d[Cha(4)]AVP (Derick et al. Endocrinology 2002, 143, 4655-4664) were evaluated on human arginine vasopressin (AVP) V(1a), V(1b), and V(2) receptors and on the human oxytocin (OT) receptor expressed in living Chinese hamster ovary (CHO) cells. Binding studies revealed that broad modifications of the fourth residue of dAVP do not significantly alter affinity for the human V(1b) receptor. Only aromatic (Phe, Tyr, Trp) or negatively charged (Glu) residues reduce V(1b) affinity. By contrast, the human V(1a) and more particularly the human V(2) and the OT receptors are more sensitive to many of these modifications. Thus, the replacement of the Gln(4) residue of dAVP by aliphatic (Leu, Cha) or positively charged (Orn, Lys, Arg, Har) amino acids led to analogues exhibiting drastic reductions of their affinity for the human V(1a), V(2), and OT receptors. Consequently, in addition to the previously reported d[Cha(4)]AVP, peptides 6 and 17-20 display excellent selectivities for the human V(1b) receptor. The key structural requirement responsible for optimal V(1b) selectivity appears to be the length and branching of the aliphatic side chain of the fourth residue of dAVP. Functional studies performed on CHO cells expressing the different human AVP/OT receptors confirm the V(1b) selectivity of peptides 6, 17, 18, 20, and d[Cha(4)]AVP. However, d[Arg(4)]AVP (19), which triggers an excellent coupling between the human V(2) receptor and adenylyl cyclase, was found to exhibit both V(1b) and V(2) agonism in functional tests. More interestingly, these functional experiments revealed that, depending on the AVP/OT receptor, a given d[X(4)]AVP analogue may behave as a full agonist or as a partial agonist. This strongly suggests that the fourth residue of dAVP plays an important role in the coupling between the hormone-receptor complex, the heterotrimeric G protein, and the effectors. In conclusion, the synthesis of these d[X(4)]AVP analogues led to the discovery of new V(1b) agonists with high affinity and greatly enhanced selectivities. Thus, in addition to d[Cha(4)]AVP, d[Leu(4)]AVP (6), d[Orn(4)]AVP (17), d[Lys(4)]AVP (18), and d[Har(4)]AVP (20) are useful new tools for studying the structure and the function of the human V(1b) receptor.
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PMID:Design of potent and selective agonists for the human vasopressin V1b receptor based on modifications of [deamino-cys1]arginine vasopressin at position 4. 1508 36

A series of in vivo studies in a conscious rat model was conducted to investigate the role of oxytocinergic and dopaminergic neurotransmission in the central regulation of penile erection. Oxytocin, when administrated either intracerebroventricularly (i.c.v.) or intrathecally (i.t.) at the spinal levels of L4-L6, produced dose-related erectogenic effects with a maximum at 0.1 microg/rat i.c.v. or 0.03 microg/rat i.t. Oxytocin-evoked penile activity was attenuated by the inhibitory effect of the selective oxytocin antagonist vasotocin analog [Pmp-Tyr(Me)-Ile-Thr-Asn-Cys]-Pro-Orn-Tyr-NH2 (0.1-1 microg, i.c.v. or i.t.). Penile erection induced by oxytocin was blocked by the dopaminergic receptor antagonist clozapine (1-10 micromol/kg i.p.) in a dose-dependent manner. Conversely, oxytocin antagonist microinjected locally (i.c.v. or i.t.) significantly attenuated the pro-erectile effects of systemic (s.c.) apomorphine, a centrally acting erectogenic agent through dopaminergic receptors. Together, these data indicate a possible concomitant role between dopamine and oxytocin in mediating penile erection at both the spinal and supraspinal sites.
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PMID:Central oxytocinergic and dopaminergic mechanisms regulating penile erection in conscious rats. 1600 55

Arginine vasopressin (AVP) mediates a wide variety of biological actions by acting on three distinct G-protein coupled receptors, termed V(1a) (vascular), V(1b) (pituitary) and V(2) (renal). It also binds to the oxytocin (OT) receptor. As part of a program aimed at the design of selective agonists for the human V(1b) receptor, we recently reported the human V(1b), V(1a), V(2) and OT receptor affinities of the following position 4 substituted analogues of [deamino-Cys(1)] arginine vasopressin (dAVP)-(1) d[Leu(4)]AVP, (2) d[Orn(4)]AVP, (3) d[Lys(4)]AVP, (4) d[Har(4)]AVP, (5) d[Arg(4)]AVP, (6) d[Val(4)]AVP, (7) d[Ala(4)]AVP, (8) d[Abu(4)]AVP, (9) d[Nva(4)]AVP, (10) d[Nle(4)]AVP, (11) d[Ile(4)]AVP, (12) d[Phe(4)]AVP, (13) d[Asn(4)]AVP, (14) d[Thr(4)]AVP: (15) d[Dap(4)]AVP. With the exception of Nos. 7 and 12, all peptides exhibit very high affinities for the human V(1b) receptor. Furthermore, peptides 1-4 exhibit high selectivities for the human V(1b) receptor with respect to the V(1a), V(2) and OT receptors and, with d[Cha(4)]AVP, in functional tests, are the first high affinity selective agonists for the human V(1b) receptor (Cheng LL et al., J. Med. Chem. 47: 2375-2388, 2004). We report here the pharmacological properties of peptides 1-4, 5 (from a resynthesis), 7, 9-13, 15 in rat bioassays (antidiuretic, vasopressor and oxytocic) (in vitro: no Mg(++)) with those previously reported for peptides 5, 6, 8, 14. We also report the rat V(1b), V(1a), V(2) and OT receptor affinities of peptides 1-5 and the rat V(2) receptor affinities for peptides: 7-15.The antidiuretic activities in units/mg of peptides 1-15, are: 1=378; 2=260; 3=35; 4=505; 5=748; 6=1150; 7=841; 8=1020; 9=877; 10=1141; 11=819, 12=110; 13=996; 14=758; 15=1053. Peptides 1-4 exhibit respectively the following rat and human (in brackets) V(2) receptor affinities: 1=3.1 nm (245 nm); 2=3.4 nm (1125 nm); 3=24.6 nm (11,170 nm); 4=0.6 nm (1386 nm). Their rat V(1b) receptor affinities are 1=0.02 nm; 2=0.45 nm; 3=9.8 nm; 4=0.32 nm. Their rat V(1a) receptor affinities are 1=1252 nm; 2=900 nm; 3=1478 nm; 4=32 nm. Their rat oxytocin (OT) receptor affinities are 1=481 nm; 2=997 nm; 3=5042 nm; 4=2996 nm. All four peptides have high affinities and selectivities for the rat V(1b) receptor with respect to the rat V(1a) and OT receptors. However, in contrast to their high selectivity for the human V(1b) receptor with respect to the human V(2) receptor, they are not selective for the V(1b) receptor with respect to the V(2) receptor in the rat. These findings confirm previous observations of profound species differences between the rat and human V(2) receptors. Peptides 1-4 are promising leads to the design of the first high affinity selective agonists for the rat V(1b) receptor.
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PMID:Position 4 analogues of [deamino-Cys(1)] arginine vasopressin exhibit striking species differences for human and rat V(2)/V(1b) receptor selectivity. 1613 Jan 78

Eleven new analogues were synthesized by modification of the potent oxytocin antagonist (OTA) [(S)Pmp(1), D-Trp(2), Pen(6), Arg(8)]-Oxytocin, or PA (parent antagonist), in which (S)Pmp = beta,beta-(3-thiapentamethylene)-beta-mercapto-propionic acid. By internal acylation of Lys, Orn, L-1,4-diaminobutyric acid (Dab), L-1,3-diaminopropionic acid (Dap) at position 4 with the C-terminal Gly of the peptide tail, we prepared cyclo-(4-9)-[Lys(4), Gly(9)]-PA (pA(2) = 8.77 +/- 0.27), 1, and cyclo-(4-9)-[Orn(4), Gly(9)]-PA (pA(2) = 8.81 +/- 0.25), 3, which are equipotent with PA (pA(2) = 8.68 +/- 0.18) in the rat uterotonic assay and cyclo-(4-9)-[Dab(4), Gly(9)]-PA, 4, cyclo-(4-9)-[Dap(4), Gly(9)]-PA, 5, and cyclo-(4-9)-[Pmp(1), Lys(4), Gly(9)]-PA, 2, which were weaker OTAs. Neither 1 nor 3 had activity as agonists or antagonists in the antidiuretic assay. In the pressor assay, both analogues 1 and 3, with pA(2) = 7.05 +/- 0.10 and pA(2) = 6.77 +/- 0.12, respectively, are somewhat weaker antagonists than PA (pA(2) = 7.47 +/- 0.35) showing significant gain in specificity. The [desamido(9)] PA-ethylenediamine monoamide, 6, and the dimer ([desamido(9)]-PA)(2) ethylenediamine diamide, 7, had lower potency in the uterotonic assay than PA. Additionally, we synthesized cyclo-(1-5)-[(HN)Pmp(1), Asp(5)]-PA, 8, inactive in all tests, which suggests that the intact Asn(5) side chain may be critical in the interaction of the OTAs with the oxytocin (OT) receptor. Similarly, cyclo-(5-9)-[Dap(5), Gly(9)]-PA, 9, had very low uterotonic potency. Two derivatives of PA truncated from the C-terminus were internally cyclized to Lys(4), giving rise to cyclo-(4-8)-desGly-NH(2)(9)[Lys(4), Arg(8)]-PA, 10 (pA(2) = 8.35 +/- 0.20), which maintains the high potency of PA and has no activity in the rat antidiuretic assay, and in the rat pressor assay it is about ten times weaker (pA2 = 6.41 +/- 0.15) than PA (pA2 = 7.47 +/- 0.35), thus showing gains in specificity, and to cyclo-(4-7)-desArg-Gly-(NH)(2)(8-9)[Lys(4), Pro(7))-PA, 11, which has much weaker potency than PA. Synthesis of cyclo-(4-6)-desPro-Arg-Gly-(NH)(2)(7-9)[Lys(4)]-PA failed.
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PMID:Design of novel bicyclic analogues derived from a potent oxytocin antagonist. 1643 6

Oxytocin (OT; Cys-Tyr-Ile-Gln-Asn-Cys-Pro-leu-Gly), a posterior pituitary peptide hormone, is characterized by a Cys1-Cys6 disulfide bond in its stable, isolated state. This paper describes a simple, one-step method for the production of OT in its reduced, dithiol form (OT dithiol), free of reducing agent. The effects of temperature, pH, and metal-ion chelators on the autoxidation of OT dithiol were examined to establish if this form is likely to persist under biological conditions. It was found that OT dithiol has a half-life of 1.8h with respect to reformation of OT disulfide at 37 degrees C and pH 6.9 in the presence of the copper chelators, DTPA and neocuproine. S-Nitrosation of OT dithiol by acidified nitrite at pH 3.0 was examined by absorption spectroscopy and HPLC-UV-MS, which revealed that both singly and doubly S-nitrosated OT are formed. These results suggest novel chemical aspects to OT signaling, the biological implications of which are discussed here.
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PMID:Reduction and S-nitrosation of the neuropeptide oxytocin: implications for its biological function. 1769 43

Eleven oxytocin analogues substituted in position 4, 5 or 9 by tetrazole analogues of amino acids were prepared using solid-phase peptide synthesis method and tested for rat uterotonic in vitro and pressor activities, as well as for their affinity to human oxytocin receptor. The tetrazolic group has been used as a bioisosteric substitution of carboxylic, ester or amide groups in structure-activity relationship studies of biologically active compounds. Replacement of the amide groups of Gln(4) and Asn(5) in oxytocin by tetrazole analogues of aspartic, glutamic and alpha-aminoadipic acids containing the tetrazole moiety in the side chains leads to analogues with decreased biological activities. Oxytocin analogues in which the glycine amide residue in position 9 was substituted by tetrazole analogues of glycine had diminished activities as well. The analysis of differences in rat uterotonic activity and in the affinity to human oxytocin receptors of analogues containing either an acidic 5-substituted tetrazolic group or a neutral 1,5- or 2,5-tetrazole nucleus makes it possible to draw some new conclusions concerning the role of the amide group of amino acids in positions 4, 5 and 9 of oxytocin for its activity. The data suggest that the interaction of the side chain of Gln(4) with the oxytocin receptor is influenced mainly by electronic effects and the hydrogen bonding capacity of the amide group. Steric effects of the side chain are minor. Substitution of Asn(5) by its tetrazole derivative gave an analogue of very low activity. The result suggests that in the interaction between the amide group of Asn(5) and the binding sites of oxytocic receptor hydrogen bonds are of less importance than the spatial requirements for this group.
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PMID:Oxytocin analogues with amide groups substituted by tetrazole groups in position 4, 5 or 9. 1808 51


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