BIOMAT Database Logo BIOMAT Database Logo

Design of potent and selective agonists for the human vasopressin V1b receptor based on modifications of [deamino-cys1]arginine vasopressin at position 4. 2004

Ling Ling Cheng, and Stoytcho Stoev, and Maurice Manning, and Sylvain Derick, and Ana Pena, and Mohamed Ben Mimoun, and Gilles Guillon
Department of Biochemistry and Molecular Biology, Medical College of Ohio, 3035 Arlington Avenue, Toledo, Ohio 43614-5804, USA.

The glutamine(4) residue in [deamino-Cys(1)]arginine vasopressin (dAVP) was replaced by a broad series of aliphatic, aromatic, polar, and charged amino acids to give the following peptides: d[Gly(4)]AVP (1), d[Ala(4)]AVP (2), d[Abu(4)]AVP (3), d[Nva(4)]AVP (4), d[Nle(4)]AVP (5), d[Leu(4)]AVP (6), d[Ile(4)]AVP (7), d[Thi(4)]AVP (8), d[Phe(4)]AVP (9), d[Tyr(4)]AVP (10), d[Trp(4)]AVP (11), d[Asn(4)]AVP (12), d[Ser(4)]AVP (13), d[Thr(4)]AVP (14), d[Dap(4)]AVP (15), d[Dab(4)]AVP (16), d[Orn(4)]AVP (17), d[Lys(4)]AVP (18), d[Arg(4)]AVP (19), d[Har(4)]AVP (20), and d[Glu(4)]AVP (21). All peptides were synthesized by solid-phase methods using BOC chemistry for all but one peptide (8), which required the use of Fmoc chemistry. The binding and functional properties of these position 4 substituted analogues of dAVP (d[X(4)]AVP) and the previously reported d[Cha(4)]AVP (Derick et al. Endocrinology 2002, 143, 4655-4664) were evaluated on human arginine vasopressin (AVP) V(1a), V(1b), and V(2) receptors and on the human oxytocin (OT) receptor expressed in living Chinese hamster ovary (CHO) cells. Binding studies revealed that broad modifications of the fourth residue of dAVP do not significantly alter affinity for the human V(1b) receptor. Only aromatic (Phe, Tyr, Trp) or negatively charged (Glu) residues reduce V(1b) affinity. By contrast, the human V(1a) and more particularly the human V(2) and the OT receptors are more sensitive to many of these modifications. Thus, the replacement of the Gln(4) residue of dAVP by aliphatic (Leu, Cha) or positively charged (Orn, Lys, Arg, Har) amino acids led to analogues exhibiting drastic reductions of their affinity for the human V(1a), V(2), and OT receptors. Consequently, in addition to the previously reported d[Cha(4)]AVP, peptides 6 and 17-20 display excellent selectivities for the human V(1b) receptor. The key structural requirement responsible for optimal V(1b) selectivity appears to be the length and branching of the aliphatic side chain of the fourth residue of dAVP. Functional studies performed on CHO cells expressing the different human AVP/OT receptors confirm the V(1b) selectivity of peptides 6, 17, 18, 20, and d[Cha(4)]AVP. However, d[Arg(4)]AVP (19), which triggers an excellent coupling between the human V(2) receptor and adenylyl cyclase, was found to exhibit both V(1b) and V(2) agonism in functional tests. More interestingly, these functional experiments revealed that, depending on the AVP/OT receptor, a given d[X(4)]AVP analogue may behave as a full agonist or as a partial agonist. This strongly suggests that the fourth residue of dAVP plays an important role in the coupling between the hormone-receptor complex, the heterotrimeric G protein, and the effectors. In conclusion, the synthesis of these d[X(4)]AVP analogues led to the discovery of new V(1b) agonists with high affinity and greatly enhanced selectivities. Thus, in addition to d[Cha(4)]AVP, d[Leu(4)]AVP (6), d[Orn(4)]AVP (17), d[Lys(4)]AVP (18), and d[Har(4)]AVP (20) are useful new tools for studying the structure and the function of the human V(1b) receptor.

UI MeSH Term Description Entries
D007295 Inositol Phosphates Phosphoric acid esters of inositol. They include mono- and polyphosphoric acid esters, with the exception of inositol hexaphosphate which is PHYTIC ACID. Inositol Phosphate,Phosphate, Inositol,Phosphates, Inositol
D010456 Peptides, Cyclic Peptides whose amino acid residues are linked together forming a circular chain. Some of them are ANTI-INFECTIVE AGENTS; some are biosynthesized non-ribosomally (PEPTIDE BIOSYNTHESIS, NON-RIBOSOMAL). Circular Peptide,Cyclic Peptide,Cyclic Peptides,Cyclopeptide,Orbitide,Circular Peptides,Cyclopeptides,Orbitides,Peptide, Circular,Peptide, Cyclic,Peptides, Circular
D003894 Deamino Arginine Vasopressin A synthetic analog of the pituitary hormone, ARGININE VASOPRESSIN. Its action is mediated by the VASOPRESSIN receptor V2. It has prolonged antidiuretic activity, but little pressor effects. It also modulates levels of circulating FACTOR VIII and VON WILLEBRAND FACTOR. Desmopressin,Vasopressin, Deamino Arginine,1-Deamino-8-D-arginine Vasopressin,1-Desamino-8-arginine Vasopressin,Adiuretin,Adiuretin SD,Apo-Desmopressin,DDAVP,Desmogalen,Desmopressin Acetate,Desmopressin Monoacetate,Desmopressin Monoacetate, Trihydrate,Desmopressine Ferring,Desmospray,Desmotabs,Minirin,Minurin,Nocutil,Octim,Octostim,Acetate, Desmopressin,Arginine Vasopressin, Deamino,Ferring, Desmopressine,Monoacetate, Desmopressin,Monoacetate, Trihydrate Desmopressin,Trihydrate Desmopressin Monoacetate,Vasopressin, 1-Deamino-8-D-arginine,Vasopressin, 1-Desamino-8-arginine
D006224 Cricetinae A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS. Cricetus,Hamsters,Hamster
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000242 Cyclic AMP An adenine nucleotide containing one phosphate group which is esterified to both the 3'- and 5'-positions of the sugar moiety. It is a second messenger and a key intracellular regulator, functioning as a mediator of activity for a number of hormones, including epinephrine, glucagon, and ACTH. Adenosine Cyclic 3',5'-Monophosphate,Adenosine Cyclic 3,5 Monophosphate,Adenosine Cyclic Monophosphate,Adenosine Cyclic-3',5'-Monophosphate,Cyclic AMP, (R)-Isomer,Cyclic AMP, Disodium Salt,Cyclic AMP, Monoammonium Salt,Cyclic AMP, Monopotassium Salt,Cyclic AMP, Monosodium Salt,Cyclic AMP, Sodium Salt,3',5'-Monophosphate, Adenosine Cyclic,AMP, Cyclic,Adenosine Cyclic 3',5' Monophosphate,Cyclic 3',5'-Monophosphate, Adenosine,Cyclic Monophosphate, Adenosine,Cyclic-3',5'-Monophosphate, Adenosine,Monophosphate, Adenosine Cyclic
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D016466 CHO Cells CELL LINE derived from the ovary of the Chinese hamster, Cricetulus griseus (CRICETULUS). The species is a favorite for cytogenetic studies because of its small chromosome number. The cell line has provided model systems for the study of genetic alterations in cultured mammalian cells. CHO Cell,Cell, CHO,Cells, CHO
D017483 Receptors, Vasopressin Specific molecular sites or proteins on or in cells to which VASOPRESSINS bind or interact in order to modify the function of the cells. Two types of vasopressin receptor exist, the V1 receptor in the vascular smooth muscle and the V2 receptor in the kidneys. The V1 receptor can be subdivided into V1a and V1b (formerly V3) receptors. Antidiuretic Hormone Receptors,Receptors, V1,Receptors, V2,V1 Receptors,V2 Receptors,Vasopressin Receptors,8-Arg-Vasopressin Receptor,Antidiuretic Hormone Receptor,Antidiuretic Hormone Receptor 1a,Antidiuretic Hormone Receptor 1b,Arginine Vasopressin Receptor,Argipressin Receptor,Argipressin Receptors,Receptor, Arginine(8)-Vasopressin,Renal-Type Arginine Vasopressin Receptor,V1 Receptor,V1a Vasopressin Receptor,V1b Vasopressin Receptor,V2 Receptor,Vascular-Hepatic Type Arginine Vasopressin Receptor,Vasopressin Receptor,Vasopressin Receptor 1,Vasopressin Type 1A Receptor,Vasopressin V1a Receptor,Vasopressin V1b Receptor,Vasopressin V2 Receptor,Vasopressin V3 Receptor,8 Arg Vasopressin Receptor,Hormone Receptor, Antidiuretic,Hormone Receptors, Antidiuretic,Receptor, Antidiuretic Hormone,Receptor, Arginine Vasopressin,Receptor, Argipressin,Receptor, V1,Receptor, V2,Receptor, Vasopressin,Receptor, Vasopressin V1b,Receptor, Vasopressin V3,Receptors, Antidiuretic Hormone,Receptors, Argipressin,Renal Type Arginine Vasopressin Receptor,V1b Receptor, Vasopressin,Vascular Hepatic Type Arginine Vasopressin Receptor,Vasopressin Receptor, V1b

Related Publications

Ling Ling Cheng, and Stoytcho Stoev, and Maurice Manning, and Sylvain Derick, and Ana Pena, and Mohamed Ben Mimoun, and Gilles Guillon
Potent and selective antagonists of the antidiuretic responses to arginine-vasopressin based on modifications of [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid),2-D-isoleucine,4- valine]arginine-vasopressin at position 4.
April 1984, Journal of medicinal chemistry,
Ling Ling Cheng, and Stoytcho Stoev, and Maurice Manning, and Sylvain Derick, and Ana Pena, and Mohamed Ben Mimoun, and Gilles Guillon
Synthesis and some pharmacological properties of deamino(4-threonine,8-D-arginine)vasopressin and deamino(8-D-arginine)vasopressin, highly potent and specific antidiuretic peptides, and (8-D-arginine)vasopressin and deamino-arginine-vasopressin.
June 1976, Journal of medicinal chemistry,
Ling Ling Cheng, and Stoytcho Stoev, and Maurice Manning, and Sylvain Derick, and Ana Pena, and Mohamed Ben Mimoun, and Gilles Guillon
Potent antagonists of the antidiuretic responses to arginine-vasopressin based on modifications of [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid),2-D- phenylalanine,4-valine]arginine-vasopressin at position 4.
November 1983, Journal of medicinal chemistry,
Ling Ling Cheng, and Stoytcho Stoev, and Maurice Manning, and Sylvain Derick, and Ana Pena, and Mohamed Ben Mimoun, and Gilles Guillon
2-O-alkyltyrosine derivatives of 1-deamino-arginine-vasopressin: highly specific and potent antidiuretic agonists.
January 1989, Journal of medicinal chemistry,
Ling Ling Cheng, and Stoytcho Stoev, and Maurice Manning, and Sylvain Derick, and Ana Pena, and Mohamed Ben Mimoun, and Gilles Guillon
Design, synthesis, and anti-tumor activity of 4'-thionucleosides as potent and selective agonists at the human A3 adenosine receptor.
January 2007, Nucleosides, nucleotides & nucleic acids,
Ling Ling Cheng, and Stoytcho Stoev, and Maurice Manning, and Sylvain Derick, and Ana Pena, and Mohamed Ben Mimoun, and Gilles Guillon
Design and synthesis of potent and selective 1,3,4-trisubstituted-2-oxopiperazine based melanocortin-4 receptor agonists.
September 2006, Bioorganic & medicinal chemistry letters,
Ling Ling Cheng, and Stoytcho Stoev, and Maurice Manning, and Sylvain Derick, and Ana Pena, and Mohamed Ben Mimoun, and Gilles Guillon
Potent and selective MC-4 receptor agonists based on a novel disulfide scaffold.
October 2005, Bioorganic & medicinal chemistry letters,
Ling Ling Cheng, and Stoytcho Stoev, and Maurice Manning, and Sylvain Derick, and Ana Pena, and Mohamed Ben Mimoun, and Gilles Guillon
1-desamino-8-D-arginine vasopressin (DDAVP) as an agonist on V1b vasopressin receptor.
June 1997, Biochemical pharmacology,
Ling Ling Cheng, and Stoytcho Stoev, and Maurice Manning, and Sylvain Derick, and Ana Pena, and Mohamed Ben Mimoun, and Gilles Guillon
Design of potent and selective antagonists of the vasopressor responses to arginine-vasopressin.
April 1982, Journal of medicinal chemistry,
Ling Ling Cheng, and Stoytcho Stoev, and Maurice Manning, and Sylvain Derick, and Ana Pena, and Mohamed Ben Mimoun, and Gilles Guillon
D-4'-thioadenosine derivatives as highly potent and selective agonists at the human A3 adenosine receptor.
January 2005, Nucleosides, nucleotides & nucleic acids,
Copied contents to your clipboard!