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Query: pept 1
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Three Tic-containing (Tic = 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) model peptides were synthesized to assess the tendency of this constrained Phe analogue to fold into a beta-bend and a helical structure, and to adopt a preferred side-chain disposition. The results of the solution conformational analysis, performed by using Fourier transform infrared absorption and 1H nuclear magnetic resonance, indicate that in chloroform the -Aib-D-Tic-Aib-, -(Aib)2-D-Tic-(Aib)2-, and -L-Pro-D-Tic- sequences fold into intramolecularly H-bonded forms to a great extent. An X-ray diffraction analysis on p-BrBz-(Aib)2-DL-Tic-(Aib)2-OMe monohydrate and p-BrBz-L-Pro-D-Tic-NHMe allows us to conclude that, while the pentapeptide methylester forms an incipient (distorted) 3(10)-helix, the dipeptide methylamide adopts a type-II beta-bend conformation. In both cases, the D-Tic side-chain conformation is D, gauche(-). The implications for the use of the Tic residue in designing conformationally restricted analogues of bioactive peptides are briefly discussed.
Int J Pept Protein Res
PMID:Constrained phenylalanine analogues. Preferred conformation of the 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) residue. 133 96

The kinetics of the spontaneous formation of 2,5-dioxopiperazines from peptides containing the Tic (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) residue in the 2-position of the sequence has been studied in DMSO and water solution. The reaction is first order in Tic-peptide and subject to general-acid catalysis. Moreover, only the fraction of peptide having the amino terminal group in the deprotonated state reacts with appreciable rate. In pure organic solvent, and in aqueous solution with low buffer concentration, the degradation reaction of Tic-peptides is very low; at 20 degrees C for the peptide H-Tyr-Tic-Phe-Phe-NH2, in DMSO and in neutral water in the absence of buffer, the half-lives (t1/2) are 3 x 10(4) and 1.2 x 10(4) h, respectively. The addition of carboxylic acids or buffers to the reaction solutions markedly increases the reaction rate; in 0.01 m HAc in DMSO and in 0.1 M phosphate buffer in water, pH 7.1, t1/2 values for the tetrapeptide are 61 and 121 h, respectively.
Int J Pept Protein Res 1995 Jun
PMID:Acid catalysis in the formation of dioxopiperazines from peptides containing tetrahydroisoquinoline-3-carboxylic acid at position 2. 755 88

A series of dermorphin analogues containing an N-alkylated amino-acid residue Xaa in the 2-position of the peptide sequence was synthesized (Xaa = N-methylalanine, proline, pipecolic acid, N-methylphenylalanine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid [Tic]). These peptides have the potential of assuming a cis Tyr1-Xaa2 peptide bond. Their in vitro opioid activity profiles were determined in mu- and delta-receptor-representative binding assays and bioassays. Aside from [D-Pro2]dermorphin, all analogues showed high affinity for mu- and/or delta-opioid receptors. Whereas most compounds were found to be full mu-agonists in the guinea pig ileum (GPI) assay, [Tic2]dermorphin (compound 7) was a partial mu-agonist. Replacement of Gly4 in 7 with Phe resulted in an analogue (8) with weak mu-antagonist activity. Furthermore, analogues 7 and 8 both were potent delta-antagonists (Ke = 3-40 nM) against the delta-agonists Leu-enkephalin, DPDPE and deltorphin I in the mouse vas deferens (MVD) assay. Compound 3, containing L-Pro in the 2-position, turned out to be one of the most mu-receptor-selective linear dermorphin analogues reported to date. Low-temperature HPLC experiments using micropellicular octadecyl silica as stationary phase revealed conformational heterogeneity of the dermorphin analogues which was ascribed to cis-trans isomerization around the Tyr1-Xaa2- and Tyr5-Pro6 peptide bonds. In the case of analogue 7 four separate peaks corresponding to the four possible isomers were apparent at -5 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)
Int J Pept Protein Res 1995 Jul
PMID:Structure-activity relationships of dermorphin analogues containing N-substituted amino acids in the 2-position of the peptide sequence. 755 96

In order to study further the importance of the P'1 residue upon the activity of human PC1 and human furin, two important members of subtilisin/kexin family of enzymes, we have prepared by solid-phase Fmoc or recently introduced FastMoc chemistry a series of 10 peptidyl substrate analogs. The structures of these analogs are based upon the core sequence of pro-mPC1(83-93) namely, D-Tyr-Lys-Glu-Arg-Ser-Lys-Arg-Xaa-Val-Gln-Lys-Asp, where D-Tyr replaces the native L-Tyr residue and Xaa, representing the P'1 position, corresponds to L-Ser or to nonproteinacous amino acids such as Tle, Sarc, MLeu, Aib, D-Tic or L-Tic. Two more analogs with L-Tic at P'1 position but with one amino acid less, namely P5 Glu or P'3 Gln, and one with a Cit residue in place of Arg at P1 site of the dodecapeptide were also obtained. These peptides were all fully characterized by a combination of MS, 1H-NMR and amino acid analysis. In contrast to the Ser analog, which is an excellent substrate for both hPC1 and hfurin, these analogs displayed moderate to strong inhibition of both hPC1 and hfurin activity in a reversible competitive manner. They all exhibited higher potency for hfurin than for hPC1, with an inhibition constant (Ki) ranging from 0.8 to 10 microM and from 1.0 to 170 microM, respectively. Incorporation of L-Tic yielded an analog with a two to four-fold increased inhibition of either enzymes when compared to its D-Tic counterpart, the effect being more pronounced for hPC1 than for hfurin. Comparison of these data with those for the corresponding N-terminal Fmoc protected peptides revealed that the highly hydrophobic N-terminal Fmoc function occupying the P8 position can contribute positively or negatively towards proteinase inhibition depending on the nature of the unnatural amino acid at P'1 and the enzyme used. Finally, none of the analogs was significantly cleaved by either enzyme. FTIR data on these analogs revealed some important structural differences between the substrate and inhibitor analogs, as there appears to be a conformational shift from a more beta-sheet-like structure for the substrates to a more alpha-helical-like structure for the inhibitors.
Int J Pept Protein Res
PMID:Peptidyl substrates containing unnatural amino acid at the P'1 position are potent inhibitors of prohormone convertases. 853 76

We have refined the 1H NMR-based conformations of the mu-opioid receptor selective peptides related to somatostatin of general formula Xxx-Yyy1-Cys-Zzz-D-Trp-Lys(Orn)5-Thr-Pen-Thr8- NH2, where Xxx, Yyy, Zzz are 0, D-Phe and Tyr for 1; 0, D-Tic and Tyr for 2; Gly, D-Tic and Tyr for 3; and 0, D-Phe and Tic for 4, respectively, (Kazmierski et al., J. Am. Chem. 113, 2275-2283), using a molecular-dynamics approach. We present evidence that the NMR data are compatible with beta II'-, gamma- and gamma'-turns for the central tetrapeptide Tyr-D-Trp-Lys/Orn-Thr. Based on detailed structural and topographical considerations, we suggest that the mu-opioid receptor selectivity of 2 is due to a particular spatial arrangement of aromatic side chains of D-Tic1 and Tyr3 (7.5 A), and that the opioid receptor recognition domain is located in the N-terminal part of the peptide while the somatostatin receptor recognition domain is determined by the central, turn forming part of this class of cyclic peptides. A model for a mu-opioid selective ligand has emerged from these studies that shows excellent structural similarities to rigid opioid alkaloids.
Int J Pept Protein Res
PMID:A topographical model of mu-opioid and brain somatostatin receptor selective ligands. NMR and molecular dynamics studies. 853 80

The beta-casomorphin-5 analog H-Tyr-c[-D-Orn-2-Nal-D-Pro-Gly-] (2-Nal = 2-naphthylalanine) was the first reported cyclic opioid peptide with mixed mu agonist/delta antagonist properties [R. Schmidt et al. (1994) J. Med. Chem. 37, 1136-1144]. The 2-Nal3 residue in this peptide was replaced with benzothienylalanine (Bta) (3), His(Bzl) (4), Tyr(Bzl) (5), 4'-benzoylphenylalanine (Bpa) (6), 4'-benzylphenylalanine (Bzp) (7), thyronine (Thy) (8), thyroxine (Thx) (9), 4'-biphenylalanine (Bip) (10), 4'-biphenylglycine (Bpg) (12) and 3,3-diphenylalanine (Dip) (14), and the in vitro opioid activity profiles of the resulting compounds were determined in mu and delta receptor-representative binding assays and bioassays. Analogues 3, 12 and 14 were full agonists in the mu receptor-representative guinea-pig ileum (GPI) assay and also were agonists in the delta receptor-representative mouse vas deferens (MVD) assay. The agonist effects of the latter compounds in the MVD assay were antagonized by the highly selective delta antagonist H-Tyr-Tic-Phe-Phe-OH (TIPP), indicating that they were triggered by delta receptor activation. The Bzp3- and Bip3- containing peptides 7 and 10 turned out to be mu antagonists against the mu selective agonist H-Tyr-D-Ala-Phe-Phe-NH2 in the GPI assay. The other analogues were weak partial mu agonists which displayed remarkably decreased mu receptor affinity as compared to parent peptide 1. Compounds 4-10 were found to be delta antagonists in the MVD assay. Analogues 4 and 9 exhibited delta antagonist potency similar to that of parent peptide 1, while compounds 5-8 and 10 showed 3-12-fold higher delta antagonist potency against DPDPE and deltorphin I and, in most cases, increased delta receptor affinity. These results indicate that the delta receptor tolerates bulky aromatic side chains in the 3-position of cyclic beta-casomorphin analogs with either delta agonist or delta antagonist properties. However, these compounds displayed drastically reduced mu receptor affinity in nearly all cases.
Int J Pept Protein Res 1996 Nov
PMID:Effect of aromatic amino acid substitutions in the 3-position of cyclic beta-casomorphin analogues on mu-opioid agonist/delta-opioid antagonist properties. 895 74

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).
J Pept Sci
PMID:Position three in vasopressin antagonist tolerates conformationally restricted and aromatic amino acid substitutions: a striking contrast with vasopressin agonists. 923 Apr 69

The formylpeptides formyl-methionyl-N-methylleucyl-phenylalanine methyl ester [for-Met-(NMe)Leu-Phe-OMe] 1, formyl-methionyl-2-aminotetralin-2-carboxyl-phenylalanine methyl ester [for-Met-Atc-Phe-OMe] 2, formyl-methionyl-1,2,3,4-tetrahydroisoquinoline-3-carboxyl-phenylalanine methyl ester [for-Met-Tic-Phe-OMe] 3 and formyl-methionyl-2-aminoxy-4-methylvaleryl-phenylalanine methyl ester [for-Met-OLeu-Phe-OMe] 4 were synthesized in order to investigate the role of the amide bond at position 2 on biological activities on human neutrophils. Only analogue 2, which keeps the NH group at position 2, was found to retain activity though sterically encumbered.
J Pept Sci
PMID:The importance of the peptide bond at position 2 in HCO-Met-Leu-Phe-OMe analogues as shown by studies on human neutrophils. 923 22

Two different models for the receptor-bound conformation of delta-opioid peptide antagonists containing the N-terminal dipeptide segment H-Tyr-Tic (Tic = 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) have been proposed. Both models are based on spatial overlap of the Tyr1 and Tic2 aromatic rings and N-terminal amino group with the corresponding aromatic rings and nitrogen atom of the nonpeptide delta-antagonist naltrindole. However, in one model the peptide bond between the Tyr1 and Tic2 residues assumes the trans conformation, whereas in the other it is in the cis conformation. To distinguish between these two models, we prepared the two peptides H-Tyr(psi)[CH2NH]Tic-Phe-Phe-OH and H-Tyr(psi)[CH2NH]MeTic-Phe-Phe-OH (MeTic = 3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) in which a cis peptide bond between the Tyr and Tic (or MeTic) residues is sterically forbidden. Both compounds turned out to be moderately potent delta-opioid antagonists in the mouse vas deferens assay. A molecular mechanics study performed with both peptides resulted in low-energy conformations in which the torsional angle ("omega1") of the reduced peptide bond between Tyr and Tic (or MeTic) had a value of 180 degrees (trans conformation) and which were in good agreement with the proposed model with all trans peptide bonds. Furthermore, this study confirmed that neither of these two peptides could assume low-energy conformations in which "omega1" had a value of 0 degrees (cis conformation). Conformers with that same bond in the gauche conformation ("omega1" = -60 degrees) were also identified, but were higher in energy and showed no spatial overlap with naltrindole. On the basis of these results it is concluded that the receptor-bound conformation of delta-peptide antagonists containing an N-terminal H-Tyr-Tic-dipeptide segment must have all trans peptide bonds.
J Pept Res 1998 May
PMID:The receptor-bound conformation of H-Tyr-Tic-(Phe-Phe)-OH-related delta-opioid antagonists contains all trans peptide bonds. 960 18

An efficient synthesis of the cyclic decapeptide MEN 11270 [H-DArg1-Arg2 Pro3-Hyp4-Gly5-Thi6-Dab7-DTic8-Oic9-Arg10 c(7gamma - 10alpha)] was developed. Two three-dimensional orthogonal strategies were applied and compared: Fmoc/Tos/Boc (procedure A) and Fmoc/Pmc/Dde (procedure B). Both resulted in a 23-step strategy comprising the stepwise solid-phase chain assembly of the linear protected peptide, partial deprotection, solution-phase cyclization and final full deprotection. The stepwise assembly of the linear peptide was optimized by double coupling and acylation time prolongation for critical residues (Tic, Dab, Thi, Pro). O-(7-azabenzotriazol-1-yl)-N,N,N',N' tetramethyluronium (HATU) was preferred as coupling reagent for Dab. In the cyclization step, the partial racemization of Arg10 (31% using 1-ethyl-3-(3'-dimethyl-aminopropyl) carbodiimide/1-hydroxybenzotriazole (EDC/HOBt) as activation system) was reduced to 3% with HATU. The final deprotection was performed in the presence of dimethylsulfide (procedure A) and thiocresol (procedure B) as scavengers, to avoid the sulfation of Hyp side chain. The final compound and the main by-products were characterized by mass spectroscopy (MS), nuclear magnetic resonance (NMR) and racemization test. Procedure B produced operationally simpler and more efficient results than A (28% overall yield versus 4%).
J Pept Sci 2000 Dec
PMID:Solid-phase synthesis of MEN 11270, a new cyclic peptide kinin B2 receptor antagonist. 1119 41


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