Peptide and non-peptide agonists and antagonists for the vasopressin and oxytocin V1a, V1b, V2 and OT receptors: research tools and potential therapeutic agents.
Oxytocin (OT) and vasopressin (AVP) mediate their biological actions by acting on four known receptors: The OT (uterine) and the AVP V(1a) (vasopressor), V(1b) (pituitary), V(2) (renal) receptors and a fifth putative AVP V(1c)? (vasodilating) receptor. This presentation will summarize some highlights of the recent progress, in the design and synthesis of selective peptide agonists, antagonists, radioiodinated ligands, fluorescent ligands and bivalent ligands for these receptors. Here we present published and unpublished pharmacological data on the most widely used agonists, antagonists and labelled ligands. The pharmacological properties of promising new selective OT antagonists and V(1b) agonists are also presented. This review should serve as a useful guide for the selection of the most appropriate ligand for a given study. The current status of non-peptide OT and AVP antagonists and agonists is also summarized. The relative merits of peptide and non-peptide AVP and OT agonists and antagonists as: (1) research tools and (2) therapeutic agents will be evaluated. Many of the receptor selective peptide agonists and antagonists from this and other laboratories are far more widely used as pharmacological tools for studies on the peripheral and central effects of OT and AVP than their non-peptide counterparts. In addition to OT and to a lesser extent AVP (pitressin), a number of OT and AVP analogues; such as carbetocin (OT agonist) dDAVP (desmopressin, V(2) agonist), terlipressin (V(1a) agonist), felypressin (V(1a) agonist) and atosiban (Tractocile OT antagonist) are also in clinical use. Despite much early promise, no non-peptide V(1a) or OT antagonists are currently in clinical trials. While a number of orally active non-peptide V(2) antagonists (Vaptans); notably, Tolvaptan, Lixivaptan and Satavaptan, are currently in Phase III clinical trials; to date, only the mixed V(2)/V(1a), antagonist Conivaptan (Vaprisol), has been approved by the US FDA for clinical use (by i.v. administration), for the treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients. Promising new non-peptide V(1b) and OT antagonists, as well as non-peptide V(2) and OT agonists are now in pre-clinical development.
Manning
Maurice
M
Biochemistry and Cancer Biology, University of Toledo College of Medicine, Toledo, OH, USA.
Stoev
Stoytcho
S
Chini
Bice
B
Durroux
Thierry
T
Mouillac
Bernard
B
Guillon
Gilles
G
D000818:Animals; D050034:Antidiuretic Agents / Q000627:therapeutic use; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D005260:Female; D006801:Humans; D007010:Hyponatremia / Q000188:drug therapy; D008236:Lypressin / Q000031:analogs & derivatives / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010121:Oxytocin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D018045:Receptors, Oxytocin / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000187:drug effects; D017483:Receptors, Vasopressin / Q000819:agonists* / Q000187:drug effects; D013329:Structure-Activity Relationship; D000077585:Terlipressin; D014599:Uterus / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000627:therapeutic use; D014667:Vasopressins / Q000494:pharmacology / Q000502:physiology
D050034:Antidiuretic Agents; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D009842:Oligopeptides; D010455:Peptides; D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin; D014665:Vasodilator Agents; C106389:conivaptan; D014667:Vasopressins; D010121:Oxytocin; D008236:Lypressin; D000077585:Terlipressin; C020731:carbetocin; D003894:Deamino Arginine Vasopressin