Dataset Information

Pharmacological characterization of FE 201874, the first selective high affinity rat V1A vasopressin receptor agonist.

ABSTRACT:

Background and purpose

Distinct vasopressin receptors are involved in different physiological and behavioural functions. Presently, no selective agonist is available to specifically elucidate the functional roles of the V1A receptor in the rat, one of the most widely used animal models. FE 201874 is a new derivative of the human selective V1A receptor agonist F180. In this study, we performed a multi-approach pharmacological and functional characterization of FE 201874 to determine whether it is selective for V1A receptors.

Experimental approach

We modified an available human selective V1A receptor agonist (F180) and determined its pharmacological properties in cell lines expressing vasopressin/oxytocin receptors (affinity and coupling to second messenger cascades), in an ex vivo model (aorta ring contraction) and in vivo in rats (proliferation of adrenal cortex glomerulosa cells and lactation).

Key results

FE 201874 exhibited nanomolar affinity for the rat V1A receptor; it was highly selective towards the rat V1B and V2 vasopressin receptors and behaved as a full V1A agonist in all the pharmacological tests performed. FE 201874 bound to the oxytocin receptor, but with moderate affinity, and behaved as an oxytocin antagonist in vitro, but not in vivo.

Conclusions and implications

On functional grounds, all the data demonstrate that FE 201874 is the first selective agonist of the rat V1A receptor isoform available. Hence, FE 201874 may have potential as a treatment for the vasodilator-induced hypotension occurring in conditions such as septic shock and could be the most suitable compound for discriminating between the behavioural effects of arginine vasopressin and oxytocin.

SUBMITTER: Marir R

PROVIDER: S-EPMC3834753 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Publications

Pharmacological characterization of FE 201874, the first selective high affinity rat V1A vasopressin receptor agonist.

Marir Rafik R Virsolvy Anne A Wisniewski Kazimierz K Mion Julie J Haddou Dominique D Galibert Evelyne E Meraihi Zahia Z Desarménien Michel G MG Guillon Gilles G

British journal of pharmacology 20130901 2

<h4>Background and purpose</h4>Distinct vasopressin receptors are involved in different physiological and behavioural functions. Presently, no selective agonist is available to specifically elucidate the functional roles of the V1A receptor in the rat, one of the most widely used animal models. FE 201874 is a new derivative of the human selective V1A receptor agonist F180. In this study, we performed a multi-approach pharmacological and functional characterization of FE 201874 to determine wheth ...[more]

PMID: 23725319

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Project description:Vasopressin is widely used for vasopressor support in septic shock patients, but experimental evidence suggests that selective V1A agonists are superior. The initial pharmacodynamic effects, pharmacokinetics, and safety of selepressin, a novel V1A-selective vasopressin analogue, was examined in a phase IIa trial in septic shock patients.This was a randomized, double-blind, placebo-controlled multicenter trial in 53 patients in early septic shock (aged ?18 years, fluid resuscitation, requiring vasopressor support) who received selepressin 1.25 ng/kg/minute (n?=?10), 2.5 ng/kg/minute (n?=?19), 3.75 ng/kg/minute (n?=?2), or placebo (n?=?21) until shock resolution or a maximum of 7 days. If mean arterial pressure (MAP) ?65 mmHg was not maintained, open-label norepinephrine was added. Co-primary endpoints were maintenance of MAP >60 mmHg without norepinephrine, norepinephrine dose, and proportion of patients maintaining MAP >60 mmHg with or without norepinephrine over 7 days. Secondary endpoints included cumulative fluid balance, organ dysfunction, pharmacokinetics, and safety.A higher proportion of the patients receiving 2.5 ng/kg/minute selepressin maintained MAP >60 mmHg without norepinephrine (about 50% and 70% at 12 and 24 h, respectively) vs. 1.25 ng/kg/minute selepressin and placebo (p?<?0.01). The 7-day cumulative doses of norepinephrine were 761, 659, and 249 ?g/kg (placebo 1.25 ng/kg/minute and 2.5 ng/kg/minute, respectively; 2.5 ng/kg/minute vs. placebo; p?<?0.01). Norepinephrine infusion was weaned more rapidly in selepressin 2.5 ng/kg/minute vs. placebo (0.04 vs. 0.18 ?g/kg/minute at 24 h, p?<?0.001), successfully maintaining target MAP and reducing norepinephrine dose vs. placebo (first 24 h, p?<?0.001). Cumulative net fluid balance was lower from day 5 onward in the selepressin 2.5 ng/kg/minute group vs. placebo (p?<?0.05). The selepressin 2.5 ng/kg/minute group had a greater proportion of days alive and free of ventilation vs. placebo (p?<?0.02). Selepressin (2.5 ng/kg/minute) was well tolerated, with a similar frequency of treatment-emergent adverse events for selepressin 2.5 ng/kg/minute and placebo. Two patients were infused at 3.75 ng/kg/minute, one of whom had the study drug infusion discontinued for possible safety reasons, with subsequent discontinuation of this dose group.In septic shock patients, selepressin 2.5 ng/kg/minute was able to rapidly replace norepinephrine while maintaining adequate MAP, and it may improve fluid balance and shorten the time of mechanical ventilation.ClinicalTrials.gov, NCT01000649 . Registered on September 30, 2009.

Dataset Information

Pharmacological characterization of FE 201874, the first selective high affinity rat V1A vasopressin receptor agonist.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Pharmacological characterization of FE 201874, the first selective high affinity rat V1A vasopressin receptor agonist.

Similar Datasets

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