Synthesis and some pharmacological properties of [4-threonine,7-glycine]oxytocin, [1-(L-2-hydroxy-3-mercaptopropanoic acid),4-threonine,7-glycine]oxytocin (hydroxy[thr4, gly7]oxytocin), and [7-glycine]oxytocin, peptides with high oxytocic-antidiuretic selectivity

Lowbridge, J.; Manning, Maurice; Haldar, Jaya; Sawyer, Wilbur H.

doi:10.1021/jm00211a025

Cited by 103 publications

(36 citation statements)

References 8 publications

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“…Our pharmacological characterizations showed that the ex citatory action of OT was mediated specifically by OT receptors in that it could only be mimicked by the OT-selective agonist [33] TG-OT (table 4) and not by other closely related peptides, AVP or OTm, even at much higher concentrations. Further more, the two OT-selective antagonists [34,35,44,45], Cvi and ETOV, blocked OT actions, but had no or little effect on AVP action (table 5).…”

Section: Discussionmentioning

confidence: 88%

“…The peptides are: OT; an OT-selective agonist [Thr4,Gly7]-OT(TG-OT) [33]; an OT metab olite neuropeptide (OTm), pGlu-Asn-Cys(Cys)-Pro-Leu-Gly-NH2; two OT-selective antagonists, [d(CH;T,Tyr(Me)\ThrJ,Tyr-NH 29]-vasotocin, or compound VI (Cvi), and [d(CH2)s,Tyr(Me)2,Om8]-vasotocin (ETOV) [34,35]; and [Arg8]-vasopressin (AVP). They were dissolved in physio logical saline to make stock solutions, which were frozen until use.…”

Section: Agentsmentioning

confidence: 99%

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Electrophysiological Actions of Oxytocin on Hypothalamic Neurons in vitro: Neuropharmacological Characterization and Effects of Ovarian Steroids

Kow¹,

Johnson²,

Ogawa³

et al. 1991

Neuroendocrinology

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Oxytocin (OT) neurotransmission in the brain has a facilitatory effect on sexual receptivity in rats. This effect of OT is dependent on priming by ovarian steroids, estrogen and progesterone. These steroids modulate OT binding in specific brain nuclei, including the ventrolateral portion of the ventromedial hypothalamic nucleus (vlVMN). In the present study, single-unit activity was recorded from the vlVMN in hypothalamic slices to characterize the electrophysiological actions of OT. To examine the effects of ovarian steroids on OT actions, we used brain slices prepared from ovariectomized rats either treated with estrogen or not, and some slices were treated with progesterone in vitro. OT had little modulatory action on neuronal responses to other agents, but affected the activity of large numbers of vlVMN units. Of those neurons affected, 94% responded with excitation. This predominant stimulatory action of OT is consistent with its lordosis-facilitating effect, because increases in the activity of VMN neurons are generally associated with the facilitation of lordosis. Pharmacological analyses with selective OT agonists and antagonists as well as structurally related peptides showed that the excitatory action of OT is mediated by OT receptors. Estradiol modulated several aspects of OT transmission. First, it increased neuronal responsiveness to OT, especially at the lowest concentration used (0.2 nM). In addition, it caused neuronal responses to OT to correlate significantly with responses to acetylcholine and norepinephrine, which also can act on the ventromedial hypothalamus to facilitate lordosis. Finally, estradiol enhanced the excitability of laterally projecting neurons, which have been implicated in lordosis. In estrogen-pretreated slices, addition of progesterone in vitro caused little further effect on responses of individual neurons to exogenous OT. Altogether, the present electrophysiological findings are consistent with the hypothesis that estrogen potentiates OT action by increasing functional OT receptors preferentially in lordosis-relevant neurons, thereby enabling OT to efficiently facilitate female reproductive behavior.

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Section: Discussionmentioning

confidence: 88%

Section: Agentsmentioning

confidence: 99%

Electrophysiological Actions of Oxytocin on Hypothalamic Neurons in vitro: Neuropharmacological Characterization and Effects of Ovarian Steroids

Kow¹,

Johnson²,

Ogawa³

et al. 1991

Neuroendocrinology

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show abstract

“…Moreover, in order to determine whether hypothalamic ventromedial neurons in this species are sensitive to oxytocin, we have carried out extracellular recordings from hypothalamic slices. The specificity of the neuronal action of oxytocin was ascertained by using a synthetic structural analogue, acting as a selective agonist (15). Part of these data have been presented a t scientific meetings (16,17).…”

mentioning

confidence: 99%

Oxytocin Excites Neurons Located in the Ventromedial Nucleus of the Guinea‐Pig Hypothalamus

Inenaga

Karman

Yamashita

et al. 1991

J Neuroendocrinology

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The area of the ventromedial nucleus of the hypothalamus in the guinea-pig was shown in autoradiographs to contain high affinity binding sites for oxytocin. In order to ascertain whether these sites may represent neuronal receptors, single-cell extracellular recordings were obtained from ventromedial neurons in coronal slices of t h e hypothalamus of adult guinea-pigs. Oxytocin applied in the nanomolar range excited about half of the neurons tested; none were inhibited. The response to the peptide was reversible and concentration-dependent. It was exerted directly since it persisted under t h e condition of synaptic isolation. Moreover, the effect was specific since it could be mimicked by a selective oxytocin agonist and since vasopressin was usually at least 10-fold weaker than oxytocin. These findings suggest that the binding sites for oxytocin detected by light microscopic autoradiography in the guinea-pig hypothalamic ventromedial nucleus represent functional receptors.In the rat brain, specific high affinity binding sites for oxytocin could be detected in various areas by light microscopic autoradiography, both in developing ( I ) and adult animals (2-5). In several of these areas, oxytoci?, was shown to excrt a neuronal effect ( I , 6 12), corroborating the view that binding sites detected by autoradiography represent, at least in part, functional receptors associated with neurons.Unexpectedly, when other species were examined, marked regional differences in the distribution of oxytocin binding sites were found ( 1 3). Thus, the ventral hippocampus and the dorsal motor nucleus of the vagus nerve were labelled in the rat but not in the guinea-pig (9, 11). In accordance with these autoradiographical data, electrophysiological recordings showed that neurons in the hippocampus and in the dorsal vagal nucleus of the rat were excited by oxytocin; in contrast, no neuronal sensitivity to this peptide was observed in the homologous area in the guinea-pig brain (9, 1 I).Amongst the regions of the rat brain which are most intensely labelled by [3H]oxytocin and by the radioiodinated selective oxytocin antagonist [1251]OTA (l4), is the hypothalamic ventromedial nucleus ( 1 , 4, 5). In the present study, we assessed whether the hypothalamic ventromedial nucleus also contains oxytocin binding sites in the guinea-pig. Moreover, in order to determine whether hypothalamic ventromedial neurons in this species are sensitive to oxytocin, we have carried out extracellular recordings from hypothalamic slices. The specificity of the neuronal action of oxytocin was ascertained by using a synthetic structural analogue, acting as a selective agonist (15). Part of these data have been presented a t scientific meetings (16,17).

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“…Nevertheless, a few substituted analogues of OT have been described which are agonists. The Gln and Pro residues at positions 4 and 7 respectively can be substituted to generate the agonist [Thr%,Gly(]OT (TGOT) [19], and the residues Ile$ and Leu) are substituted by Phe$ and Arg) in the naturally occurring agonist analogue AVP. The [∆2-23]OTR construct exhibited wild-type affinity for both TGOT and AVP (Table 2 ; Figure 3A and 3B).…”

Section: The Distal Segment Of the Otr N-terminus Is Important For Bimentioning

confidence: 99%

“…Nevertheless, receptor-selective agonists have been developed. For example, TGOT [19] and POVT [22] are selective for the OTR and the V "a R respectively (Figures 5A and 5B). Given that a segment of the N-terminus of the OTR which is essential for high-affinity agonist binding has been defined above, it was of interest to investigate if this extracellular segment also provides the molecular basis for these receptor-selective agonists.…”

Section: The Pharmacological Characteristics Of the Wild-type Otr Arementioning

confidence: 99%

Identification of an extracellular segment of the oxytocin receptor providing agonist-specific binding epitopes

Hawtin

Howard

Wheatley

2001

Biochemical Journal

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The effects of the peptide hormone oxytocin are mediated by oxytocin receptors (OTRs) expressed by the target tissue. The OTR is a member of the large family of G-protein-coupled receptors. Defining differences between the interaction of agonists and antagonists with the OTR at the molecular level is of fundamental importance, and is addressed in this study. Using truncated and chimaeric receptor constructs, we establish that a small 12-residue segment in the distal portion of the N-terminus of the human OTR provides important epitopes which are required for agonist binding. In contrast, this segment does not contribute to the binding site for antagonists, whether peptide or non-peptide. It does, however, have a role in agonist-induced OTR signalling. Oxytocin is also an agonist at the vasopressin V1a receptor (V1aR). A chimaeric receptor (V1aRN-OTR) was engineered in which the N-terminus of the OTR was substituted by the corresponding, but unrelated, sequence from the N-terminus of the V1aR. We show that the V1aR N-terminus present in V1aRN-OTR fully restored both agonist binding and intracellular signalling to a dysfunctional truncated OTR construct. The N-terminal segment does not, however, contribute to receptor-selective agonism between the OTR and the V1aR. Our data establish a key role for the distal N-terminus of the OTR in providing agonist-specific binding epitopes.

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Synthesis and some pharmacological properties of [4-threonine,7-glycine]oxytocin, [1-(L-2-hydroxy-3-mercaptopropanoic acid),4-threonine,7-glycine]oxytocin (hydroxy[thr4, gly7]oxytocin), and [7-glycine]oxytocin, peptides with high oxytocic-antidiuretic selectivity

Cited by 103 publications

References 8 publications

Electrophysiological Actions of Oxytocin on Hypothalamic Neurons in vitro: Neuropharmacological Characterization and Effects of Ovarian Steroids

Electrophysiological Actions of Oxytocin on Hypothalamic Neurons in vitro: Neuropharmacological Characterization and Effects of Ovarian Steroids

Oxytocin Excites Neurons Located in the Ventromedial Nucleus of the Guinea‐Pig Hypothalamus

Identification of an extracellular segment of the oxytocin receptor providing agonist-specific binding epitopes

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