The Experts below are selected from a list of 3102 Experts worldwide ranked by ideXlab platform
Carlo Alberto Maggi - One of the best experts on this subject based on the ideXlab platform.
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Characterization of the tachykinin neurokinin-2 receptor in the human urinary bladder by means of selective receptor antagonists and peptidase inhibitors.
Journal of Pharmacology and Experimental Therapeutics, 1993Co-Authors: S. Giuliani, Antonio Giachetti, Laura Quartara, Gabriele Barbanti, Paolo Rovero, Riccardo Patacchini, Damiano Turini, Carlo Alberto MaggiAbstract:The tachykinin (NK2) receptor-mediating contraction of the human isolated bladder to NKA was investigated by studying the affinities of eight structurally different receptor-selective antagonists (linear peptides, cyclic peptides and Pseudopeptides, nonpeptide NK2 receptor antagonists). The affinities of the antagonists were compared to those measured for the same ligands at the NK2 receptors previously characterized in the rabbit pulmonary artery and hamster trachea. In the presence of a cocktail of peptidase inhibitors (bestatin captopril and thiorphan, 1 microM each) no significant correlation was found between pA2 values measured in the human bladder vs. those measured in the other two NK2 receptor-bearing preparation. In the presence of the aminopeptidase inhibitor amastatin, however, pA2 values of linear antagonists bearing an N-terminal Asp residue MEN 10,207 and MEN 10,376 were significantly enhanced and these pA2 values were used for analysis; a significant correlation was found between pA2 values measured in the human urinary bladder and rabbit pulmonary artery. The Pseudopeptide analog of NKA (4-10), MDL 28,564 which also bears a N-terminal Asp residue behaved as an agonist and its action was enhanced by amastatin. We conclude that the NK2 receptor-mediating contraction of the human urinary bladder smooth muscle is similar to that previously characterized in the rabbit pulmonary artery (NK2A receptor category); in the human bladder smooth muscle an amastatin-sensitive peptidase (possibly aminopeptidase A) limits biological activity of linear peptide derivatives of NKA bearing a N-terminal Asp residue.
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Characterization of the tachykinin neurokinin-2 receptor in the human urinary bladder by means of selective receptor antagonists and peptidase inhibitors.
Journal of Pharmacology and Experimental Therapeutics, 1993Co-Authors: S. Giuliani, Antonio Giachetti, Laura Quartara, Gabriele Barbanti, Paolo Rovero, Riccardo Patacchini, Damiano Turini, Carlo Alberto MaggiAbstract:The tachykinin (NK2) receptor-mediating contraction of the human isolated bladder to NKA was investigated by studying the affinities of eight structurally different receptor-selective antagonists (linear peptides, cyclic peptides and Pseudopeptides, nonpeptide NK2 receptor antagonists). The affinities of the antagonists were compared to those measured for the same ligands at the NK2 receptors previously characterized in the rabbit pulmonary artery and hamster trachea. In the presence of a cocktail of peptidase inhibitors (bestatin captopril and thiorphan, 1 microM each) no significant correlation was found between pA2 values measured in the human bladder vs. those measured in the other two NK2 receptor-bearing preparation. In the presence of the aminopeptidase inhibitor amastatin, however, pA2 values of linear antagonists bearing an N-terminal Asp residue MEN 10,207 and MEN 10,376 were significantly enhanced and these pA2 values were used for analysis; a significant correlation was found between pA2 values measured in the human urinary bladder and rabbit pulmonary artery. The Pseudopeptide analog of NKA (4-10), MDL 28,564 which also bears a N-terminal Asp residue behaved as an agonist and its action was enhanced by amastatin. We conclude that the NK2 receptor-mediating contraction of the human urinary bladder smooth muscle is similar to that previously characterized in the rabbit pulmonary artery (NK2A receptor category); in the human bladder smooth muscle an amastatin-sensitive peptidase (possibly aminopeptidase A) limits biological activity of linear peptide derivatives of NKA bearing a N-terminal Asp residue.
Keun-hyeung Lee - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of antibacterial Pseudopeptides with less hemolytic activity from a cytotoxic peptide and their pH-dependent activity.
Bioorganic & medicinal chemistry letters, 2009Co-Authors: Sung-min Kim, Joung-min Kim, Hyeongjin Cho, Keun-hyeung LeeAbstract:Abstract We synthesized antibacterial Pseudopeptides with less hemolytic activity by incorporation of reduced amide bond ψ[CH 2 NH ] into α helical antibacterial peptide with hemolytic activity. As the p K a value of reduced amide bond is 7–8, it is protonated depending on the pH. We investigated the secondary structure, the binding affinity and the leakage activity for the vesicles, and the antibacterial activity of the peptide and its Pseudopeptides at neutral and basic pH. Unlike the peptide, the Pseudopeptides showed a more potent leakage activity when pH increased. The peptide exhibited a lower antibacterial activity at basic pH than at neutral pH, whereas the Pseudopeptide showed the same antibacterial activity at basic and neutral pH. Overall results indicated that hydrophobicity of backbone of the Pseudopeptide plays an important role in the increase of leakage activity and retention of antibacterial activity at basic pH.
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Application of microwave method to the solid phase synthesis of Pseudopeptides containing ester bond
Tetrahedron Letters, 2008Co-Authors: Bishnu P. Joshi, Jun-won Park, Joung-min Kim, Chuda Raj Lohani, Hyeongjin Cho, Keun-hyeung LeeAbstract:Abstract A new procedure was developed for reducing the reaction time and improving the yield of esterification reaction in solid phase synthesis of Pseudopeptides containing an ester bond by utilizing microwave irradiation. We selected a pseudodipeptide (Fmoc-LysΨ[COO]Leu-NH2) and optimized the microwave-assisted esterification reaction in solid phase synthesis using Fmoc chemistry. For this, microwave-assisted esterification reactions with different reaction time, temperature, and solvents were performed using 1,3-diisopropylcarbodiimide (DIC) as the coupling reagent. We synthesized several pseudodipeptides containing an ester bond by using the optimized microwave irradiation method. The purity and yield of the pseudodipeptides synthesized in this way were better than those obtained without microwave irradiation. Furthermore, we applied this methodology for synthesizing Pseudopeptides (6- and 12-mer) corresponding to the α helical peptide. The microwave-assisted esterification reaction afforded the target Pseudopeptides with high yield (∼80%) and purity within 12 min, whereas the reaction without microwave irradiation afforded the target compound with poor yield (∼45%) and low purity.
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Microwave-assisted solid-phase synthesis of Pseudopeptides containing reduced amide bond
Tetrahedron Letters, 2007Co-Authors: Mi-sun Park, Hyeongjin Cho, Keun-hyeung LeeAbstract:Abstract Procedures were developed for reducing the reaction time and improving the yield of reductive alkylation in solid phase Pseudopeptide synthesis by utilizing microwave irradiation. We chose dipeptides containing the reduced amide bond ψ[CH 2 NH] as a model system and optimized the microwave assisted reductive alkylation reaction in solid phase Pseudopeptide synthesis using Fmoc chemistry. Under the optimized condition, the reductive alkylation reaction used for incorporating the reduced amide bond into the dipeptides was completed in only 8.5 min, whereas the normal reductive alkylation reaction required a total of 300 min. The purity and yield of the various dipeptides containing the reduced amide bond synthesized in this way are better than those achieved using the reductive alkylation method without microwave irradiation. We chose α helical peptides, which are known as a difficult sequence to synthesize, and incorporated the reduced amide bond by the microwave-assisted reductive alkylation reaction. We successfully synthesized Pseudopeptides containing the reduced amide bond as a major product by using the novel microwave-assisted method, whereas the same products were obtained as a minor product when using the reductive alkylation method without microwave irradiation.
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Design and synthesis of novel antimicrobial Pseudopeptides with selective membrane-perturbation activity
Bioorganic & medicinal chemistry, 2000Co-Authors: Keun-hyeung LeeAbstract:By incorporating carbamate bond(s) into a cytolytic peptide, novel Pseudopeptides with potent antibacterial activity and low hemolytic activity were synthesized. Circular dichroism spectra suggested that the incorporation of carbamate bond(s) decrease the α helical conformation of the peptide in lipid membrane circumstances, which must be regarded as a major factor for the separation of antibacterial activity from cytotoxic activity for mammalian cell. Experiments in which dye was released from vesicles indicated that the potent antibacterial activity and low hemolytic activity of the Pseudopeptides must be due to their great lipid membrane selectivity. The present result suggest that backbone modifications can be a great tool for developing Pseudopeptides with improved biological activity and bioavailability from cytolytic peptides.
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The comparison of characteristics between membrane-active antifungal peptide and its Pseudopeptides.
Bioorganic & medicinal chemistry, 1999Co-Authors: Sung Yu Hong, Keun-hyeung LeeAbstract:By the introduction of various amide surrogates, novel Pseudopeptides corresponding to a membrane active depsipeptide were synthesized and their native characteristics compared with that of the peptide. The Pseudopeptides had more resistance to serum proteases than the peptide and similar antimicrobial activities to that of the peptide without hemolytic activity. The Pseudopeptides like the peptide were active against current drug resistant fungi and pathogenic fungi isolated from patients, and also had a strong synergism with current antifungal drugs against Candida albicans. The leakage assay suggested that the Pseudopeptides also acted on the lipid membrane of pathogenic cells. These results indicated that the novel Pseudopeptides had advantages over the peptide as a candidate for a novel antifungal drug and backbone modifications can be a tool in the development of a novel antifungal agent from membrane-active peptides isolated from natural sources or chemically synthesized.
L. Devel - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and Structural/Functional Characterization of Selective M14 Metallocarboxypeptidase Inhibitors Based on Phosphinic Pseudopeptide Scaffold: Implications on the Design of Specific Optical Probes
Journal of medicinal chemistry, 2019Co-Authors: Giovanni Covaleda, Pablo Gallego, Josep Vendrell, Dimitris Georgiadis, Julia Lorenzo, Vincent Dive, Francesc X. Avilés, David Reverter, L. DevelAbstract:Metallocarboxypeptidases (MCPs) of the M14 family are Zn2+-dependent exoproteases present in almost every tissue or fluid in mammals. These enzymes perform a large variety of physiological functions and are involved in several pathologies, such as pancreatic diseases, inflammation, fibrinolysis, and cancer. Here, we describe the synthesis and functional/structural characterization of a series of reversible tight-binding phosphinic Pseudopeptide inhibitors that show high specificity and potency toward these proteases. Characterization of their inhibitory potential against a large variety of MCPs, combined with high-resolution crystal structures of three selected candidates in complex with human carboxypeptidase A (CPA)1, allowed to decipher the structural determinants governing selectivity for type-A of the M14A MCP family. Further, the phosphinic Pseudopeptide framework was exploited to generate an optical probe selectively targeting human CPAs. The phosphinic Pseudopeptides presented here constitute the ...
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synthesis and structural functional characterization of selective m14 metallocarboxypeptidase inhibitors based on phosphinic Pseudopeptide scaffold implications on the design of specific optical probes
Journal of Medicinal Chemistry, 2019Co-Authors: Giovanni Covaleda, Pablo Gallego, Josep Vendrell, Dimitris Georgiadis, Julia Lorenzo, Vincent Dive, Francesc X. Avilés, David Reverter, L. DevelAbstract:Metallocarboxypeptidases (MCPs) of the M14 family are Zn2+-dependent exoproteases present in almost every tissue or fluid in mammals. These enzymes perform a large variety of physiological functions and are involved in several pathologies, such as pancreatic diseases, inflammation, fibrinolysis, and cancer. Here, we describe the synthesis and functional/structural characterization of a series of reversible tight-binding phosphinic Pseudopeptide inhibitors that show high specificity and potency toward these proteases. Characterization of their inhibitory potential against a large variety of MCPs, combined with high-resolution crystal structures of three selected candidates in complex with human carboxypeptidase A (CPA)1, allowed to decipher the structural determinants governing selectivity for type-A of the M14A MCP family. Further, the phosphinic Pseudopeptide framework was exploited to generate an optical probe selectively targeting human CPAs. The phosphinic Pseudopeptides presented here constitute the ...
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Synthesis and Structural/Functional Characterization of Selective M14 Metallocarboxypeptidase Inhibitors Based on Phosphinic Pseudopeptide Scaffold: Implications on the Design of Specific Optical Probes
2019Co-Authors: Giovanni Covaleda, Pablo Gallego, Josep Vendrell, Dimitris Georgiadis, Julia Lorenzo, Vincent Dive, Francesc X. Avilés, David Reverter, L. DevelAbstract:Metallocarboxypeptidases (MCPs) of the M14 family are Zn2+-dependent exoproteases present in almost every tissue or fluid in mammals. These enzymes perform a large variety of physiological functions and are involved in several pathologies, such as pancreatic diseases, inflammation, fibrinolysis, and cancer. Here, we describe the synthesis and functional/structural characterization of a series of reversible tight-binding phosphinic Pseudopeptide inhibitors that show high specificity and potency toward these proteases. Characterization of their inhibitory potential against a large variety of MCPs, combined with high-resolution crystal structures of three selected candidates in complex with human carboxypeptidase A (CPA)1, allowed to decipher the structural determinants governing selectivity for type-A of the M14A MCP family. Further, the phosphinic Pseudopeptide framework was exploited to generate an optical probe selectively targeting human CPAs. The phosphinic Pseudopeptides presented here constitute the first example of chemical probes useful to selectively report on type-A MCPs activity in complex media
Riccardo Patacchini - One of the best experts on this subject based on the ideXlab platform.
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Activity of cyclic Pseudopeptide antagonists at peripheral tachykinin receptors.
The Journal of pharmacology and experimental therapeutics, 1995Co-Authors: Riccardo Patacchini, Antonio Giachetti, Laura Quartara, M. Astolfi, Cristina Goso, C.a. MaggiAbstract:The cyclic Pseudopeptides MEN 10,548, MEN 10,581, MEN 10,619, MEN 10,677, MEN 10,777 and MEN 10,867 were studied at tachykinin neurokinin (NK)1, NK2 and NK3 receptors on several in vitro bioassays. All compounds were potent and competitive antagonists at tachykinin NK1 and NK2 receptors of the guinea-pig ileum, rabbit pulmonary artery and hamster trachea, showing the highest affinity for the hamster NK2 receptor (e.g., MEN 10,677: pKB = 9.3). By contrast, none showed affinity for NK3 receptors of the rat portal vein, up to 3 microM. In the guinea-pig isolated bronchus, the Pseudopeptide compounds competitively antagonized the NK2 receptor-selective agonist [beta Ala8]-NKA (4-10) with potencies comparable to those shown at the rabbit NK2 receptor. In addition, the Pseudopeptides were from 3.5-fold (MEN 10,677) to 16-fold (MEN 10548) more potent antagonists against septide than against [Sar9]SP sulfone, two agonists reportedly selective for two distinct sites/subtypes of the NK1 receptor. In binding experiments at human IM9 cells, the Pseudopeptide compounds displaced [3H]substance P from human NK1 receptor, showing similar affinities to those displayed at the NK1 receptor in the guinea-pig ileum or bronchus against substance P methylester or septide, as agonists, respectively. This new class of Pseudopeptide antagonists, by showing a comparable and high affinity at both tachykinin NK1 and NK2 receptors, might be proposed for treatment/prevention of airway diseases in which endogenous tachykinins play a role by activation of both receptors.
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Characterization of the tachykinin neurokinin-2 receptor in the human urinary bladder by means of selective receptor antagonists and peptidase inhibitors.
Journal of Pharmacology and Experimental Therapeutics, 1993Co-Authors: S. Giuliani, Antonio Giachetti, Laura Quartara, Gabriele Barbanti, Paolo Rovero, Riccardo Patacchini, Damiano Turini, Carlo Alberto MaggiAbstract:The tachykinin (NK2) receptor-mediating contraction of the human isolated bladder to NKA was investigated by studying the affinities of eight structurally different receptor-selective antagonists (linear peptides, cyclic peptides and Pseudopeptides, nonpeptide NK2 receptor antagonists). The affinities of the antagonists were compared to those measured for the same ligands at the NK2 receptors previously characterized in the rabbit pulmonary artery and hamster trachea. In the presence of a cocktail of peptidase inhibitors (bestatin captopril and thiorphan, 1 microM each) no significant correlation was found between pA2 values measured in the human bladder vs. those measured in the other two NK2 receptor-bearing preparation. In the presence of the aminopeptidase inhibitor amastatin, however, pA2 values of linear antagonists bearing an N-terminal Asp residue MEN 10,207 and MEN 10,376 were significantly enhanced and these pA2 values were used for analysis; a significant correlation was found between pA2 values measured in the human urinary bladder and rabbit pulmonary artery. The Pseudopeptide analog of NKA (4-10), MDL 28,564 which also bears a N-terminal Asp residue behaved as an agonist and its action was enhanced by amastatin. We conclude that the NK2 receptor-mediating contraction of the human urinary bladder smooth muscle is similar to that previously characterized in the rabbit pulmonary artery (NK2A receptor category); in the human bladder smooth muscle an amastatin-sensitive peptidase (possibly aminopeptidase A) limits biological activity of linear peptide derivatives of NKA bearing a N-terminal Asp residue.
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Characterization of the tachykinin neurokinin-2 receptor in the human urinary bladder by means of selective receptor antagonists and peptidase inhibitors.
Journal of Pharmacology and Experimental Therapeutics, 1993Co-Authors: S. Giuliani, Antonio Giachetti, Laura Quartara, Gabriele Barbanti, Paolo Rovero, Riccardo Patacchini, Damiano Turini, Carlo Alberto MaggiAbstract:The tachykinin (NK2) receptor-mediating contraction of the human isolated bladder to NKA was investigated by studying the affinities of eight structurally different receptor-selective antagonists (linear peptides, cyclic peptides and Pseudopeptides, nonpeptide NK2 receptor antagonists). The affinities of the antagonists were compared to those measured for the same ligands at the NK2 receptors previously characterized in the rabbit pulmonary artery and hamster trachea. In the presence of a cocktail of peptidase inhibitors (bestatin captopril and thiorphan, 1 microM each) no significant correlation was found between pA2 values measured in the human bladder vs. those measured in the other two NK2 receptor-bearing preparation. In the presence of the aminopeptidase inhibitor amastatin, however, pA2 values of linear antagonists bearing an N-terminal Asp residue MEN 10,207 and MEN 10,376 were significantly enhanced and these pA2 values were used for analysis; a significant correlation was found between pA2 values measured in the human urinary bladder and rabbit pulmonary artery. The Pseudopeptide analog of NKA (4-10), MDL 28,564 which also bears a N-terminal Asp residue behaved as an agonist and its action was enhanced by amastatin. We conclude that the NK2 receptor-mediating contraction of the human urinary bladder smooth muscle is similar to that previously characterized in the rabbit pulmonary artery (NK2A receptor category); in the human bladder smooth muscle an amastatin-sensitive peptidase (possibly aminopeptidase A) limits biological activity of linear peptide derivatives of NKA bearing a N-terminal Asp residue.
Antonio Giachetti - One of the best experts on this subject based on the ideXlab platform.
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Activity of cyclic Pseudopeptide antagonists at peripheral tachykinin receptors.
The Journal of pharmacology and experimental therapeutics, 1995Co-Authors: Riccardo Patacchini, Antonio Giachetti, Laura Quartara, M. Astolfi, Cristina Goso, C.a. MaggiAbstract:The cyclic Pseudopeptides MEN 10,548, MEN 10,581, MEN 10,619, MEN 10,677, MEN 10,777 and MEN 10,867 were studied at tachykinin neurokinin (NK)1, NK2 and NK3 receptors on several in vitro bioassays. All compounds were potent and competitive antagonists at tachykinin NK1 and NK2 receptors of the guinea-pig ileum, rabbit pulmonary artery and hamster trachea, showing the highest affinity for the hamster NK2 receptor (e.g., MEN 10,677: pKB = 9.3). By contrast, none showed affinity for NK3 receptors of the rat portal vein, up to 3 microM. In the guinea-pig isolated bronchus, the Pseudopeptide compounds competitively antagonized the NK2 receptor-selective agonist [beta Ala8]-NKA (4-10) with potencies comparable to those shown at the rabbit NK2 receptor. In addition, the Pseudopeptides were from 3.5-fold (MEN 10,677) to 16-fold (MEN 10548) more potent antagonists against septide than against [Sar9]SP sulfone, two agonists reportedly selective for two distinct sites/subtypes of the NK1 receptor. In binding experiments at human IM9 cells, the Pseudopeptide compounds displaced [3H]substance P from human NK1 receptor, showing similar affinities to those displayed at the NK1 receptor in the guinea-pig ileum or bronchus against substance P methylester or septide, as agonists, respectively. This new class of Pseudopeptide antagonists, by showing a comparable and high affinity at both tachykinin NK1 and NK2 receptors, might be proposed for treatment/prevention of airway diseases in which endogenous tachykinins play a role by activation of both receptors.
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Characterization of the tachykinin neurokinin-2 receptor in the human urinary bladder by means of selective receptor antagonists and peptidase inhibitors.
Journal of Pharmacology and Experimental Therapeutics, 1993Co-Authors: S. Giuliani, Antonio Giachetti, Laura Quartara, Gabriele Barbanti, Paolo Rovero, Riccardo Patacchini, Damiano Turini, Carlo Alberto MaggiAbstract:The tachykinin (NK2) receptor-mediating contraction of the human isolated bladder to NKA was investigated by studying the affinities of eight structurally different receptor-selective antagonists (linear peptides, cyclic peptides and Pseudopeptides, nonpeptide NK2 receptor antagonists). The affinities of the antagonists were compared to those measured for the same ligands at the NK2 receptors previously characterized in the rabbit pulmonary artery and hamster trachea. In the presence of a cocktail of peptidase inhibitors (bestatin captopril and thiorphan, 1 microM each) no significant correlation was found between pA2 values measured in the human bladder vs. those measured in the other two NK2 receptor-bearing preparation. In the presence of the aminopeptidase inhibitor amastatin, however, pA2 values of linear antagonists bearing an N-terminal Asp residue MEN 10,207 and MEN 10,376 were significantly enhanced and these pA2 values were used for analysis; a significant correlation was found between pA2 values measured in the human urinary bladder and rabbit pulmonary artery. The Pseudopeptide analog of NKA (4-10), MDL 28,564 which also bears a N-terminal Asp residue behaved as an agonist and its action was enhanced by amastatin. We conclude that the NK2 receptor-mediating contraction of the human urinary bladder smooth muscle is similar to that previously characterized in the rabbit pulmonary artery (NK2A receptor category); in the human bladder smooth muscle an amastatin-sensitive peptidase (possibly aminopeptidase A) limits biological activity of linear peptide derivatives of NKA bearing a N-terminal Asp residue.
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Characterization of the tachykinin neurokinin-2 receptor in the human urinary bladder by means of selective receptor antagonists and peptidase inhibitors.
Journal of Pharmacology and Experimental Therapeutics, 1993Co-Authors: S. Giuliani, Antonio Giachetti, Laura Quartara, Gabriele Barbanti, Paolo Rovero, Riccardo Patacchini, Damiano Turini, Carlo Alberto MaggiAbstract:The tachykinin (NK2) receptor-mediating contraction of the human isolated bladder to NKA was investigated by studying the affinities of eight structurally different receptor-selective antagonists (linear peptides, cyclic peptides and Pseudopeptides, nonpeptide NK2 receptor antagonists). The affinities of the antagonists were compared to those measured for the same ligands at the NK2 receptors previously characterized in the rabbit pulmonary artery and hamster trachea. In the presence of a cocktail of peptidase inhibitors (bestatin captopril and thiorphan, 1 microM each) no significant correlation was found between pA2 values measured in the human bladder vs. those measured in the other two NK2 receptor-bearing preparation. In the presence of the aminopeptidase inhibitor amastatin, however, pA2 values of linear antagonists bearing an N-terminal Asp residue MEN 10,207 and MEN 10,376 were significantly enhanced and these pA2 values were used for analysis; a significant correlation was found between pA2 values measured in the human urinary bladder and rabbit pulmonary artery. The Pseudopeptide analog of NKA (4-10), MDL 28,564 which also bears a N-terminal Asp residue behaved as an agonist and its action was enhanced by amastatin. We conclude that the NK2 receptor-mediating contraction of the human urinary bladder smooth muscle is similar to that previously characterized in the rabbit pulmonary artery (NK2A receptor category); in the human bladder smooth muscle an amastatin-sensitive peptidase (possibly aminopeptidase A) limits biological activity of linear peptide derivatives of NKA bearing a N-terminal Asp residue.
