The vasopressin V1a receptor: a single target with proof-of-concept across distinct clinical domains.
Arginine vasopressin (AVP) acts as a neurotransmitter in the brain and a neurohormone released into the bloodstream that regulates water retention. Substantial evidence demonstrates AVP's central role in circuits dysregulated in affective disorders, neurological insults like TBI, and in chronic stress responses.
Three subtypes — one CNS-relevant target.
AVP binds three G protein-coupled receptors. V1a is the dominant and most widely expressed subtype in limbic and cortical brain regions and is central to fear-threat circuitry and acute injury biology.
V1a receptor
- Dominant AVP receptor in limbic system and cortex
- Central to stress and threat-response circuitry
V1b receptor
- Limbic system and pituitary gland
- Implicated in HPA-axis modulation
- Distinct pharmacology from V1a
V2 receptor
- Located on collecting ducts of nephrons in kidney
- Cardiovascular therapeutic target
- Outside the CNS V1a biology focus
Circuit modulation and injury modification.
A single mechanism — V1a antagonism — addresses two distinct pathologies.
Normalizing dysregulated threat circuitry.
V1a activation amplifies threat-response circuitry in the brain. Excess AVP–V1a signaling contributes to pathological aggression and emotional dysregulation. V1a antagonism normalizes circuit function — without sedation.
Interrupting the secondary injury cascade.
TBI triggers BBB disruption, AQP4 dysregulation, and elevated AVP–V1a signaling that drives the secondary injury cascade over hours to days that leads to cellular damage, neuroinflammation, and concussion-related psychiatric symptoms and cognitive issues. V1a antagonism interrupts this cascade by blocking the dysregulation of AQP4, reducing downstream cellular damage, neuroinflammation, and limiting/preventing post-concussion syndrome.
First-in-class V1a antagonists.
CNS-penetrating, high-affinity, high-selectivity, orally bioavailable. A translational human Experimental Medicine fMRI study confirmed robust CNS effects after oral dosing in circuits dysregulated in stress-related disorders.
AVN849 / SRX251
- Injury-modifying program for mild TBI
- Reduced neuronal injury in translational mTBI model
- Prevented cognitive deficits post-injury
SRX246
- Phase 2 enrolling in Fragile X Syndrome (DoD-funded)
- Phase 2 complete in Huntington's Disease (aggression)
- Phase 2 complete in Intermittent Explosive Disorder
- FDA Orphan Drug + Fast Track designations for HD
Development supported by the National Institutes of Health (multiple SBIR grants, National Toxicology Evaluation Program, RAID, NINDS NeuroNext), the Department of Defense Congressionally Directed Medical Research Program, and private venture capital.
Replicated across two aggression phenotypes.
Clinically meaningful reduction in aggression.
- Primary, secondary, and exploratory endpoints met
- Conducted with NINDS NeuroNext network across 22 sites
- Clean safety and tolerability profile
Reduction in disability and severe aggression episodes.
- Decrease in aggression-related disability days
- Reduction in severe aggression episodes and anxiety
- Excellent tolerability and safety
Replication across independent populations confirms V1a modulation of threat circuitry. External early clinical data from Neumora Therapeutics support V1a antagonism in Alzheimer's disease agitation.
SRX251 reduces edema and preserves cognition.
In a translational momentum-exchange mTBI model (Kulkarni 2020; Morrison 2019), SRX251 demonstrated injury-modifying effects when administered acutely after injury.
Cerebral edema
After mild TBI, treatment 15 minutes after injury significantly reduced edema at 2 and 6 hours.
Cognitive function
After moderate TBI, treatment at 2 and 6 hours after injury prevented decline in Novel Object Recognition and Barnes Maze performance.