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1.
Endocrinology ; 148(9): 4136-46, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17495006

ABSTRACT

Recently, we synthesized and characterized the first selective V(1b) vasopressin (VP)/oxytocin receptor agonist, d[Cha(4)]arginine vasopressin. However, this agonist was only selective for the human receptors. We thus decided to design a selective V(1b) agonist for the rodent species. We started from previous observations showing that modifying [deamino(1),Arg(8)]VP in positions 4 and 8 altered the rat VP/oxytocin receptor selectivity. We synthesized a series of 13 [deamino(1),Arg(8)]VP analogs modified in positions 4 and 8. Among them, one seemed very promising, d[Leu(4), Lys(8)]VP. In this paper, we describe its pharmacological and physiological properties. This analog exhibited a nanomolar affinity for the rat, human, and mouse V(1b) VP receptors and a strong V(1b) selectivity for the rat species. On AtT20 cells stably transfected with the rat V(1b) receptor, d[Leu(4), Lys(8)]VP behaved as a full agonist on both phospholipase C and MAPK assays. Additional experiments revealed its ability to induce the internalization of enhanced green fluorescent protein-tagged human and mouse V(1b) receptors as expected for a full agonist. Additional physiological experiments were performed to further confirm the selectivity of this peptide. Its antidiuretic, vasopressor, and in vitro oxytocic activities were weak compared with those of VP. In contrast, used at low doses, its efficiency to stimulate adrenocorticotropin or insulin release from mouse pituitary or perfused rat pancreas, respectively, was similar to that obtained with VP. In conclusion, d[Leu(4), Lys(8)]VP is the first selective agonist available for the rat V(1b) VP receptor. It will allow a better understanding of V(1b) receptor-mediated effects in rodents.


Subject(s)
Lypressin/analogs & derivatives , Receptors, Oxytocin/agonists , Receptors, Vasopressin/agonists , Adenylyl Cyclases/metabolism , Animals , CHO Cells , Cricetinae , Cricetulus , Female , Humans , Kidney/drug effects , Kidney/physiology , Lactation , Liver/drug effects , Liver/physiology , Lypressin/chemical synthesis , Lypressin/pharmacology , Mammary Glands, Animal/drug effects , Mammary Glands, Animal/physiology , Mice , Pituitary Gland, Anterior/drug effects , Pituitary Gland, Anterior/physiology , Rats , Rats, Wistar , Receptors, Oxytocin/drug effects , Receptors, Oxytocin/genetics , Recombinant Proteins/agonists , Recombinant Proteins/drug effects , Transfection
2.
Stress ; 6(3): 199-206, 2003 Sep.
Article in English | MEDLINE | ID: mdl-13129813

ABSTRACT

By activating three distinct vasopressin receptor isoforms called V1a-R, V1b-R (V3-R) and V2-R, vasopressin (VP) mediates a wide number of biological effects in mammals and may be involved in several pathological states. Up to now only specific V1a and V2 receptor agonists and antagonists have been successfully designed. The role of the V1b-R still remains partially unknown, due to the lack of selective V1b-R ligands and orally-active molecules, which are crucial tools for investigating the central and peripheral functions or pathological disorders associated with this receptor. In this review, we report the biological and pharmacological properties of the first two specific V1b-R ligands: d[Cha4] AVP, a high affinity V1b-R agonist and SSR149415, a potent orally-active V1b-R antagonist with good selectivity with respect to other VP/OT receptor isoforms and able to control ACTH secretion in vitro and in vivo. Indeed, these molecules constitute invaluable tools for exploring the central and peripheral roles of VP mediated via V1b receptors. Interestingly, SSR149415 displays potent anxiolytic and antidepressant-like activities, indicating that this new class of drugs has a promising therapeutical potential in the treatment of stress-related disorders, anxiety and depression.


Subject(s)
Antidiuretic Hormone Receptor Antagonists , Arginine Vasopressin/analogs & derivatives , Arginine Vasopressin/pharmacology , Indoles/pharmacology , Pyrrolidines/pharmacology , Receptors, Vasopressin/agonists , Animals , Humans
3.
J Pharmacol Exp Ther ; 300(3): 1122-30, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11861823

ABSTRACT

(2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine carboxamide (SSR149415), the first selective, nonpeptide vasopressin V1b receptor antagonist yet described, has been characterized in vitro and in vivo. SSR149415 showed competitive nanomolar affinity for animal and human V1b receptors and exhibited much lower affinity for rat and human V1a, V2, and oxytocin receptors. Moreover, this compound did not interact with a large number of other receptors, enzymes, or ion channels. In vitro, SSR149415 behaved as a full antagonist and potently inhibited arginine vasopressin (AVP)-induced Ca2+ increase in Chinese hamster ovary cells expressing rat or human V1b receptors. The in vivo activity of SSR149415 has been studied in several models of elevated corticotropin secretion in conscious rats. SSR149415 inhibited exogenous AVP-induced increase in plasma corticotropin, from 3 mg/kg i.p. and 10 mg/kg p.o. upwards. Similarly, this compound antagonized AVP-potentiated corticotropin release provoked by exogenous corticoliberin at 3 mg/kg p.o. The effect lasted for more than 4 h at 10 mg/kg p.o. showing a long-lasting oral effect. SSR149415 (10 mg/kg p.o.) also blocked corticotropin secretion induced by endogenous AVP increase subsequent to body water loss. Moreover, 10 mg/kg i.p SSR149415 inhibited plasma corticotropin elevation after restraint-stress in rats by 50%. In the four-plate test, a mouse model of anxiety, SSR149415 (3 mg/kg p.o. upwards) displayed anxiolytic-like activity after acute and 7-day repeated administrations. Thus, SSR149415 is a potent, selective, and orally active V1b receptor antagonist. It represents a unique tool for exploring the functional role of V1b receptors and deserves to be clinically investigated in the field of stress and anxiety.


Subject(s)
Antidiuretic Hormone Receptor Antagonists , Adrenocorticotropic Hormone/metabolism , Animals , Anti-Anxiety Agents/pharmacology , Arginine Vasopressin/pharmacology , CHO Cells , Cattle , Cell Membrane/drug effects , Cell Membrane/metabolism , Cells, Cultured , Cricetinae , Dehydration/metabolism , Humans , Hypothalamus/drug effects , Hypothalamus/metabolism , In Vitro Techniques , Kinetics , Male , Morpholines/antagonists & inhibitors , Morpholines/pharmacology , Rats , Rats, Sprague-Dawley , Spiro Compounds/antagonists & inhibitors , Spiro Compounds/pharmacology , Stress, Psychological/metabolism
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