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Biomedical subjects

M Manning

Publications and source records attributed to M Manning.

At least 19 recordsLinked to original sources
PubMed1992

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↗
PubMed1992

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↗
PubMed1992

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↗
PubMed1991

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↗
PubMed1991

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↗
PubMed1990

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↗
PubMed1990

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.

Child↗
PubMed1990

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↗
PubMed1990

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↗
PubMed1989

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↗
PubMed1989

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↗
PubMed1989

The disadvantages of dextrality for intelligence.

The right shift (RS) theory of handedness suggests that the human bias to dextrality has costs as well as benefits. Samples of children from six primary schools were individually tested for hand preference, hand skill and Raven's Matrices. Scores on standardized educational tests recently given by teachers were available for three schools. When children were stratified for ability, the distributions of hand preference and of right minus left (R-L) hand skill were as expected if extent of RS is inversely related to ability. When children were classified for R-L score, the most strongly dextral children were poorer than all others for Matrices, English and several other tests. The trend for ability to decline from left to right across the laterality continuum was consistent for all scores available. Strong dextrality is associated with weak left-hand skill, not good right-hand skill, in accord with the hypothesis that the costs of RS are to the right hemisphere. The findings and their interpretation are discussed in comparison with Geschwind's theory of developmental pathology, and for their implications for theories of hemisphere specialization.

Cerebral Cortex↗
PubMed1988

125I-d(CH2)5[Tyr(Me)2, Tyr(NH2)9]AVP: iodination and binding characteristics of a vasopressin receptor ligand.

A radioiodinated vasopressin antagonist, d(CH2)5[Tyr(NH2)9]AVP has been prepared. Iodination was carried out at the phenyl moiety of the tyrosylamide residue at position 9, followed by HPLC purification. Non-radiolabelled monoiodinated antagonist was used as a reference for identification. 125I-d(CH2)5[Tyr(Me)2, Tyr(NH2)9]AVP binding appeared to take place with a dissociation constant of 0.28 +/- 0.09 nM (Kd +/- SD) to V1 vasopressin receptors on rat liver membranes.

Animals↗
PubMed1988

125I-labelled d(CH2)5[Tyr(Me)2,Thr4,Tyr-NH2(9)]OVT: a selective oxytocin receptor ligand.

An oxytocic antagonist, [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid,2-O-methyltyrosine,4-threonine, 8-ornithine,9-tyrosylamide]vasotocin (d(CH2)5[Tyr(Me)2, Thr4,Tyr-NH2(9)]OVT [corrected], was monoiodinated at the phenyl moiety of the tyrosylamide residue at position 9. 125I-labelling was performed with 1,3,4,6-tetrachloro-3 alpha,6 alpha-diphenyl-glycoluril. Iodination resulted in an increased affinity for rat uterine oxytocin receptors. A considerably lower affinity for rat vascular V1- and renal V2-receptors was found, resulting in a highly specific oxytocin receptor ligand. 125I-labelled d(CH2)5[Tyr(Me)2,Thr4,Tyr-NH2(9)]OVT [corrected] was demonstrated to bind selectively to one population of binding sites in rat uterus and ventral hippocampal membrane preparations. Dissociation constants ranged between 0.03 and 0.06 nM. After 3 days of exposure autoradiography revealed binding in regions known to contain oxytocin receptors as well as labelling in some new regions, while no binding was found in the lateral septum, a structure containing mainly [8-arginine]vasopressin receptors. The high specific radioactivity of 125I-labelling allowed important reductions in membrane protein amount, gain in precision of binding analysis as well as considerably lower exposure times for autoradiography.

Animals↗
PubMed1988

Novel linear antagonists of the antidiuretic (V2) and vasopressor (V1) responses to vasopressin.

We report the solid phase synthesis of a series of 16 linear analogues of the cyclic antagonist of the antidiuretic (V2) and the vasopressor (V1) responses to arginine vasopressin (AVP), d(CH2)5[D-Tyr(Et)2, Val4]AVP(A). Peptide 1, the linear precursor of (A), (CH2)5(SH)-CH2-CO-D-Tyr(Et)-Phe-Val-Asn-Cys-Pro-Arg-Gly-NH2 was modified at position six with alpha-L-aminobutyric acid (Abu) to give peptide 2. Further modifications of the Abu6 analogue (No. 2) at position one by substituting cyclohexylacetic acid (Caa), cyclohexylpropionic acid (Cpa), 1-adamantaneacetic acid (Aaa), phenylacetic acid (Phaa), tert.-butylacetic acid (t-Baa), isovaleric acid (Iva), propionic acid (Pa), L-penicillamine (P), tert.-butoxycarbonyl (Boc) or omitting any substituent at this position, and/or in combination with Arg-NH2(9), Ala-NH2(9), D-Arg8-Arg-NH2(9), and desGly9 modifications yielded the remaining 14 peptides. All 16 peptides were examined for agonistic and antagonistic potencies in AVP V2 and V1 assays in rats. Apart from the Cpa analogue and the analogue lacking any substituent in the 1-position, all exhibit substantial V2 and V1 antagonism. A number are as potent as (A) as V2 antagonists. With an anti-V2 pA2 = 8.11 +/- 0.07, Aaa-D-Tyr(Et)-Phe-Val-Asn-Abu-Pro-Arg-Arg-NH2 (No. 6) is as potent as any cyclic AVP V2 antagonist reported to date. The PaI analogue of No. 6 exhibits promising anti-V2/anti-V1 selectivity. These findings prove conclusively that a ring structure is not a requirement for recognition of or for binding to AVP V2 or V1 receptors. This discovery thus offers a promising new approach to the design of peptide and non-peptide antagonists of AVP and perhaps also to other cyclic peptides such as somatostatin, atrial-natriuretic factor, insulin, and the recently discovered endothelin. Some of these linear antagonists may be of value as pharmacological tools and as therapeutic agents.

Amino Acid Sequence↗