Receptor-specific antagonists of vasopressin and oxytocin. A current perspective.
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Animals↗
Biomedical subjects
M Manning
Publications and source records attributed to M Manning.
Design of cyclic and linear peptide antagonists of vasopressin and oxytocin: current status and future directions.
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Amino Acid Sequence↗
A general correspondence approach to apparent motion.
A general framework is considered for how different features of image parts determine the perceived direction of apparent motion between these parts as a function of their internalized feature weights. It is shown how the compatibility and constraints between pairwise part correspondences also play important roles in the types of perceived motion between parts; this process is modelled via a multivariate constraint-satisfaction procedure.
Adult↗
Oxytocin receptor subtypes in the pregnant rat myometrium and decidua: pharmacological differentiations.
Oxytocin (OT) has a dual action in the uterus: a uterotonic action on myometrial cells and a prostaglandin (PG)-releasing action on endometrial/decidual cells. It had not been determined whether the OT-binding sites or receptors on the myometrial and the endometrial/decidual membranes are of the same type or may represent two subtypes. Our studies presented in this paper show that isolated day 19-22 pregnant rat uterine horns and myometrial tissues (uterine horns with decidual tissues removed) incubated in Kreb's buffer at 37 C released PGF2 alpha in sustained quantities into the bathing medium. OT stimulated PG release over the basal release rate in a dose-dependent manner in the whole uterine horn but not in the myometrial tissue. Two OT antagonists, P[Phe(Me)2,Thr4]ornithine vasotocin (antagonist A) and desGly-NH2(9),d(CH2)5(1)[Tyr(Me)2,Thr4]ornithine vasotocin (antagonist B) were found to have different effects on the PG-releasing action of OT. At antiuterotonic doses, antagonist A had no antagonism of the PG-releasing action of OT. On the contrary, antagonist A was found to stimulate uterine PG release. Antagonist B was a full OT antagonist. At equivalent antiuterotonic doses, antagonist B inhibited both the uterotonic action and the PG-releasing action of OT. These findings suggest that OT-sensitive PGs are synthesized/released principally in the endometrium/decidua. The myometrial uterotonic OT receptors and the endometrial/decidual PG-releasing OT receptors are two distinct subtypes and can be differentiated. The existence of two OT receptor subtypes in the uterus has important implications in the clinical application of OT antagonists as tocolytics for preterm labor. To be efficacious, OT antagonist therapy needs to block both the uterotonic and the PG-releasing action of OT.
Animals↗
Design, synthesis and some uses of receptor-specific agonists and antagonists of vasopressin and oxytocin.
Selective agonists and antagonists are powerful tools for studies on AVP and OT receptors and on the physiological and pathophysiological roles of AVP and OT. Here we show how some of these peptides and their radiolabelled derivatives were designed. We also present examples of the currently available cyclic and linear OT and AVP agonists and antagonists from our laboratories.
Amino Acid Sequence↗
Potent V2/V1a vasopressin antagonists with C-terminal ethylenediamine-linked retro-amino acids.
We report the solid-phase synthesis and antagonistic potencies of 25 analogues (1-25) of [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid),2-O-ethyl-D-tyrosine,4-valine]arginine-vasopressin (d(CH2)5D-Tyr(Et)2-VAVP) (A) and of the related Ile4 (D) and [D-Phe2,Ile4] (E) analogues, potent antagonists of the antidiuretic (V2-receptor) and of the vasopressor (V1a-receptor) responses to arginine-vasopressin (AVP). Six of these peptides (1, 13, 17, 19, 21, and 23) have the Pro-Arg-Gly-NH2 tripeptide side chain fully or partially replaced or extended by ethylenediamine (Eda). The remaining 19 peptides have L- or D-amino acids retrolinked to these six C-terminal Eda peptides. Peptides 1, 13, 17, and 19 all have the ring structure of (A). Their side-chain structures are as follows: 1, Eda; 13, Pro-Eda; 17, Pro-Arg-Eda; 19, Arg-Gly-Eda. Peptide 21 is the Pro-Arg-Eda analogue of D; peptide 23 is the Pro-Arg-Gly-Eda analogue of E. Peptide 2 is the retro-Arg analogue of 1. Its side-chain structure is Eda<--Arg. Peptides 3-6 are analogues of 2 which have the D-Tyr-(Et)2 residue replaced by L-Tyr(Et)2 (3), D-Phe2 (4), D-Ile2 (5), or D-Leu2 (6), respectively. Peptides 7-12 are analogues of 2 which have the C-terminal retro-Arg replaced in retrofashion by D-Arg (7), Gly (8), Orn (9), D-Orn (10), D-Lys (11), or Arg-Arg (12). Peptides 14-16 have D-Orn (14), D-Lys (15), and D-Arg (16) retrosubstituted to peptide 13. Peptides 18, 20, and 22 are the retro-Arg-substituted analogues of 17, 19, and 21, respectively. Peptides 24 and 25 have Val and D-Val in retrolinkage with 23, respectively. All 25 peptides were examined for agonistic and antagonistic potencies in AVP V2/V1a assays. With the exception of peptides 5 and 6, all exhibit potent anti-V1a antagonism, with anti-V1a pA2 values in the range 7.64-8.33.(ABSTRACT TRUNCATED AT 400 WORDS)
Amino Acid Sequence↗
Synthesis and some pharmacological properties of potent and selective antagonists of the vasopressor (V1-receptor) response to arginine-vasopressin.
We report the solid-phase synthesis of eight position-9-modified analogues of the potent V1-receptor antagonist of arginine-vasopressin, [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid),2-O-methyltyrosine]arginine-vasopressin (d(CH2)5Tyr(Me)AVP) (1-8) and five position-9-modified analogues of the closely related beta,beta-dimethyl less potent V1 antagonist, [1-deaminopenicillamine,2-O-methyltyrosine]arginine-vasopressin (dPTyr(Me)AVP) (9-13). In d(CH2)5Tyr(Me)AVP the C-terminal Gly-NH2 was replaced by (1) ethylenediamine (Eda), (2) methylamine (NHMe), (3) Ala-NH2, (4) Val-NH2, (5) Arg-NH2, (6) Thr-NH2, (7) Gly-Eda, (8) Gly-N-butylamide (Gly-NH-Bu); in dPTyr(Me)AVP the C-terminal Gly-NH2 was replaced by (9) Ala-NH2, (10) Val-NH2, (11) Thr-NH2, (12) Arg-NH2, and (13) Tyr-NH2. All 13 analogues were tested for agonistic and antagonistic activities in in vivo rat vasopressor (V1-receptor) and rat antidiuretic (V2-receptor) assays. They exhibit no evident vasopressor agonism. All modifications in both antagonists were well-tolerated with excellent retention of V1 antagonism and striking enhancements in anti-V1/anti-V2 selectivity. With anti-V1 pA2 values of 8.75, 8.73, 8.86, and 8.78, four of the analogues of d-(CH2)5Tyr(Me)AVP (1-3 and 6) are equipotent with d(CH2)5Tyr(Me)AVP (anti-V1 pA2 = 8.62) but retain virtually none of the V2 agonism of d(CH2)5Tyr(Me)AVP. They are in fact weak V2 antagonists and strong V1 antagonists with greatly enhanced selectivity for V1 receptors relative to that of d(CH2)5Tyr(Me)AVP. With anti-V1 pA2 values respectively of 8.16, 8.05, 8.04, 8.52, and 8.25, all five analogues (9-13) of dPTyr(Me)AVP are at least as potent V1 antagonists as dPTyr(Me)AVP (pA2 = 7.96) and three of these (9, 12, 13) actually show enhanced V1 antagonism over that of dPTyr(Me)AVP. In fact, the Arg-NH2(9) analogue (12) is almost equipotent with d(CH2)5Tyr(Me)AVP. These new V1 antagonists are potentially useful as pharmacological tools for studies on the cardiovascular roles of AVP. Furthermore the analogues of dPTyr(Me)AVP may be useful in studies on the role(s) of AVP in the V1b-receptor-mediated release of ACTH from corticotrophs.
Amino Acid Sequence↗
Extracorporeal shock wave lithotripsy of ureteric stones with the Modulith SL 20.
A series of 138 patients with ureteric calculi was treated by in situ extracorporeal shock wave lithotripsy (ESWL) during the clinical introduction of the Modulith SL 20. This machine represents a newly developed lithotriptor with an electromagnetic cylinder as shock wave source and a dual localisation system consisting of in-line ultrasound and an integrated fluoroscope C-arm. During the first 2 months, 12 patients (phase 1) were treated under ultrasound localisation alone; during the next 5 months, 37 patients (phase 2) were treated using dual imaging modalities with reduced peak pressure (max. 18 kV = 800 bar); during the final 7 months, 89 patients (phase 3) were treated under ultrasonic and fluoroscopic localisation combined with an increased maximal shock wave pressure (20 kV = 1024 bar). The introduction of fluoroscopic targeting (phases 2 and 3) resulted in satisfactory localisation of calculi in the mid-ureter, previously limited by use of only coaxial ultrasound. The extension of stone localisation to the whole length of the ureter was associated with a marked decrease in treatment time, reflecting the easy handling of the dual localisation system. The rise in generator voltage (phase 3) improved the disintegration rate from 81% (phase 2) to 85%, whereas the number of impulses remained unchanged. However, the rate of auxiliary procedures following ESWL (adjuvant and curative) was reduced from 33% (phase 2) to 24.5%. Thus the Modulith SL 20 in its final design enables in situ ESWL to be the treatment of choice for all ureteric calculi, rendering special positioning techniques or multiple treatment unnecessary.
Humans↗
A radioiodinated linear vasopressin antagonist: a ligand with high affinity and specificity for V1a receptors.
A linear vasopressin antagonist, Phaa-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (Linear AVP Antag) (Phaa = Phenylacetyl), was monoiodinated at the phenyl moiety of the tyrosylamide residue at position 9. This antagonist appeared to be a highly potent anti-vasopressor peptide with a pA2 value in vivo of 8.94. It was demonstrated to bind to rat liver membrane preparations with a very high affinity (Kd = 0.06 nM). The affinity for the rat uterus oxytocin receptor was lower (Ki = 2.1 nM), and affinities for the rat kidney- and adenohypophysis-vasopressin receptors were much lower (Ki = 47 nM and 92 nM, respectively), resulting in a highly specific vasopressin V1a receptor ligand. Autoradiographical studies using rat brain slices showed that this ligand is a good tool for studies on vasopressin receptor localization and characterization.
Amino Acid Sequence↗
Cyclic and linear vasopressin V1 and V1/V2 antagonists containing arginine in the 4-position.
Substitution of arginine for glutamine in the 4-position of a vasopressin V1 antagonist has been reported to turn it into an agonist. We resynthesized this 4-arginine analog and synthesized additional cyclic and linear vasopressin antagonists containing a 4-arginine. The presence of a 4-arginine in the resynthesized and new analogs had relatively minor effects on their antivasopressin V1 and V2 antagonistic potencies.
Amino Acid Sequence↗
Invertebrate neuropeptides resembling vasotocin and some analogues: synthesis and pharmacological properties.
The solid phase synthesis of three invertebrate vasopressin-oxytocin homologs: AVP-like factor, F1(1), ([Leu2, Thr4] AVT)2 isolated from subesophageal and thoracic ganglia of Locusta migratoria3, Arg-conopressin-S4. ([Ile2, Arg4] AVT), Lys-conopressin-G4 ([Phe2, Arg4] LVT), both isolated from the venom of fish-hunting marine snails of the genus Conus and six of their analogues is reported. These analogues are: [Arg4] AVT, [Ile2] AVT, [Leu2] AVT, [Phe2, Arg4] AVT, [Arg4] LVT and [Ile2, Arg4] LVT. All peptides were tested for antidiuretic and vasopressor activities.
Animals↗
Arithmetic and laterality.
Relationships between arithmetic ability, hand preference and hand skill were investigated in a general population sample of schoolchildren, aged 9-11 years. Incidences of non-right-handedness were highest in the children best at arithmetic and fell progressively through average and below average groups. Strong effects were found for hand skill; level of ability declined linearly from left to right across the R-L continuum in both sexes. Strong dextrality was associated with poor left hand skill and not superior right hand skill. Arithmetic ability was positively associated with left hand skill but not with right hand skill.
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Design of potent and selective linear antagonists of vasopressor (V1-receptor) responses to vasopressin.
We report the solid-phase synthesis of 21 linear analogues of A and D, two nonselective antagonists of the vasopressor (V1) and antidiuretic (V2) responses to arginine vasopressin (AVP). A is Aaa-D-Tyr(Et)-Phe-Val-Asn-Abu-Pro-Arg-Arg-NH2 (where Aaa = adamantylacetyl at position 1). D is the des-Arg9 analogue of A. Nine new analogues of A (1-9) and 12 new analogues of D (10-21) were obtained. The following substitutions either alone or in combination were incorporated in A and/or in D: phenylacetic acid (Phaa) and tert-butylacetic acid (t-Baa) at position 1; D-Tyr2, D-Tyr(Me)2; Gln4; Arg6, Lys6, Orn6, MeAla7. The nine new analogues of A are (1) [Arg6], (2) [Lys6], (3) [Orn6], (4) [Phaa1,Lys6], (5) [Phaa1,Orn6], (6) [D-Tyr2], (7) [D-Tyr2,Arg6], (8) [Phaa1,D-Tyr2], (9) [Phaa1,D-Tyr2,Arg6]. The 12 new analogues of D are (10) [Arg6], (11) [Lys6], (12) [Orn6], (13) [Phaa1,Lys6], (14) [Phaa1,Gln4,Lys6], (15) [Phaa,D-Tyr(Me)2,Lys6], (16) [Phaa,D-Tyr(Me)2,Gln4,Lys6], (17) [Phaa1,D-Tyr2,Gln4,Lys6], (18) [t-Baa1,Lys6], (19) [t-Baa1,Gln4,Lys6], (20) [Arg6,MeAla7], (21) [t-Baa1,Arg6,MeAla7]. All 21 peptides were examined for agonistic and antagonistic potencies in AVP V2 and V1 assays in rats. With the exception of 6, the eight remaining new analogues of A are equipotent or more potent than A as V1 antagonists. Peptides 2-9 are less potent than A as V2 antagonists. Three, 4, 5, and 9, exhibit significant gains in anti-V1/anti-V2 selectivities (selectivity ratio = 41, 14, and infinite, respectively), compared to A (anti-V1, pA2 = 7.75 +/- 0.07; selectivity ratio = 0.44). Peptide 9 is unique in both series. It is a highly potent V1 antagonist (anti-V1 pA2 = 8.62 +/- 0.11 and is the first linear peptide to exhibit substantial antidiuretic agonism (4.1 +/- 0.2 units/mg). With the exception of 12, the remaining 11 analogues of D are 8-40 times more potent than D as V1 antagonists. Eight of these peptides exhibit significant gains in anti-V1/anti-V2 selectivities compared to D (anti-V1 pA2 = 7.43 +/- 0.06; selectivity ratio = 1.6).(ABSTRACT TRUNCATED AT 400 WORDS)
Amino Acid Sequence↗
Reading and a balanced polymorphism for laterality and ability.
The idea that reading ability might vary with right-left hand skill, such that children with mild biases to the right hand have advantages for learning, while children at both left and right extremes have disadvantages, was supported by findings for a large sample of primary schoolchildren. Poor readers tended to have weak left hand skills, giving strong right hand preferences in many cases. Those with additionally poor right hand skills tended to be of low intelligence. Good left hand skills and raised incidences of mixed and left hand preference were found only in a small subgroup, "bright dyslexics".
Aptitude↗
2-O-alkyltyrosine derivatives of 1-deamino-arginine-vasopressin: highly specific and potent antidiuretic agonists.
We report the solid-phase synthesis of eight 2-O-alkyltyrosine analogues of 1-deamino-arginine-vasopressin (dAVP) with enhanced antidiuretic agonistic specificity. These peptides are as follows: 1-deamino[2-O-methyltyrosine]-arginine-vasopressin (dTyr(Me)AVP), 1-deamino[2-O-ethyltyrosine]arginine-vasopressin (dTyr(Et)AVP), 1-deamino[2-O-methyltyrosine,8-D-arginine]vasopressin (dTyr(Me)DAVP), 1-deamino[2-O-ethyltyrosine,8-D-arginine]vasopressin (dTyr(Et)DAVP), 1-deamino[2-O-methyltyrosine,4-valine]arginine-vasopressin (dTyr(Me)VAVP), 1-deamino[2-O-ethyltyrosine,4-valine]arginine-vasopressin (dTyr(Et)VAVP), 1-deamino[2-O-methyltyrosine,4-valine,8-D-arginine]vasopressin (dTyr(Me)VDAVP), and 1-deamino[2-O-ethyltyrosine,4-valine,8-D-arginine]vasopressin (dTyr(Et)VDAVP). All analogues were tested for antidiuretic, antivasopressor, and antioxytocic activities. Deamination, as was expected, significantly enhanced the antidiuretic properties of these analogues relative to their parent N-amino-O-alkyltyrosine peptides. With the exception of dTyr(Me)AVP, all of these analogues are antagonists of the vasopressor responses to AVP and of the uterine response to oxytocin. Thus they all exhibit high antidiuretic agonistic specificity. Due to its remarkable properties, dTyr(Me)VDAVP is a unique compound in this series. It appears to be the most potent antidiuretic agonist (1740 units/mg) and also a vasopressor antagonist and a potent oxytocin antagonist. It is thus a highly specific antidiuretic agonist. In general, all of these new analogues are highly specific and thus are potentially useful as pharmacological tools and clinical agents.
Animals↗
Solid-phase synthesis of 16 potent (selective and nonselective) in vivo antagonists of oxytocin.
We describe the synthesis and some pharmacological properties of 16 new in vivo antagonists of oxytocin. These are based on modifications of three peptides: A, B, and C. A is our previously reported potent and selective antagonist of the vasopressor (V1 receptor) responses to arginine-vasopressin (AVP)/weak oxytocin antagonist, [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid), 2-O-methyltyrosine]arginine-vasopressin (d(CH2)5[Tyr(Me)2]AVP. B reported here, the Ile3 analogue of A, is d(CH2)5[Tyr(Me)2]AVT (5 below) and C is our previously reported potent nonselective oxytocin antagonist/AVP V1 antagonist, [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid),2-O- methyltyrosine,8-ornithine]vasotocin (d(CH2)5[Tyr(Me)2]OVT). The following substitutions and deletions, alone or in combination, were employed in A, B, and C: 1-deaminopenicillamine (dP); D-Tyr(Alk)2 (where Alk = Me or Et), D-Phe2; Val4, Thr4; delta 3-Pro7; Lys8, Cit8; desGly9, desGly-NH2(9), Ala-NH2(9); Leu-NH2(9); Arg-NH2(9). The 16 new analogues are (1) d(CH2)5[D-Tyr(Me)2]AVP, (2) d(CH2)5[D-Tyr(Me)2, Val4,delta 3-Pro7]AVP, (3) d(CH2)5[D-Tyr-(Et)2, Val4,Lys8]VP, (4) d(CH2)5[D-Tyr(Et)2,Val4,Cit8]VP, (5) d(CH2)5[Tyr(Me)2]AVT, (6) d(CH2)5[Tyr(Me)2,Lys8]VT, (7) dP[Tyr(Me)2]AVT, (8) dP[Tyr(Me)2,Val4]AVT, (9) d(CH2)5[D-Tyr(Me)2, Val4]AVT, (10) d(CH2)5[D-Phe2,Val4]AVT, (11) d(CH2)5[Tyr(Me)2,Thr4]OVT, (12) d(CH2)5[Tyr(Me)2,Thr4,Ala-NH2(9)]OVT, (13) d(CH2)5[Tyr(Me)2,Thr4,Leu-NH2(9)]OVT, (14) d(CH2)5[Tyr(Me)2,Thr4,Arg-NH2(9)]OVT, (15) desGly-NH2(9),d(CH2)5[Tyr(Me)2,Thr4]OVT, (16) desGly9,d(CH2)5[Tyr(Me)2,Thr4]OVT. 1-4 are analogues of A, 5-10 are analogues of B, and 11-16 are analogues of C. Their protected precursors were synthesized either entirely by the solid-phase method or by a combination of solid-phase and solution methods (1 + 8 or 8 + 1 couplings). All analogues were tested in rats for agonistic and antagonistic activities in oxytocic (in vitro, without and with Mg2+, and in vivo) assays as well as by antidiuretic and vasopressor assays. All analogues exhibit potent oxytocic antagonism in vitro and in vivo. With an in vitro pA2 (in the absence of Mg2+) = 9.12 +/- 0.09, dP[Tyr(Me)2]AVT is (7) one of the most potent in vitro oxytocin antagonists reported to date. Fifteen of these analogues (all but 6) appear as potent or more potent in vivo oxytocin antagonists than C (pA2 = 7.37 +/- 0.17). Analogues 1-9 and 14 are potent AVP V1 antagonists. Their anti-V1 pA2 values range from 7.92 to 8.45. They are thus nonselective oxytocin antagonists.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
The shoulder after radical neck dissection.
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