Investigating Serotonin Function:

• Serotonin Receptor Agonist: Quipazine acts as a non-selective serotonin receptor agonist, meaning it directly stimulates various types of serotonin receptors in the brain. This allows researchers to study the effects of serotonin activation on different neural processes .
• Modeling Serotonin-Related Disorders: By mimicking the effects of serotonin, quipazine can be used to model certain aspects of serotonin-related disorders like depression and anxiety in animal models .

Studying Neural Signaling:

• Head-Twitch Response: Quipazine induces a characteristic “head-twitch” response in rodents, which is a specific behavioral endpoint used to assess drug effects on serotonin signaling pathways .
• Investigating Gq/11 Signaling: Recent research suggests quipazine may influence a specific signaling pathway in the brain called the Gq/11 pathway, which is involved in various cellular functions .

Other Potential Applications:

• Antidepressant Potential: Quipazine was initially investigated as a potential antidepressant due to its serotonin-modulating effects; however, it was never developed for clinical use .
• Oxytocic Effects: Limited research suggests quipazine may also have oxytocic properties, meaning it could potentially stimulate uterine contractions, but further investigation is needed .

Quipazine is a compound belonging to the piperazine family, primarily recognized for its serotonergic activity. Initially developed as an antidepressant, it has garnered attention in scientific research due to its interaction with various serotonin receptors, particularly the 5-HT2A and 5-HT3 subtypes. Its chemical formula is C13H15N3C13​H15​N3​, with a molar mass of approximately 213.284 g/mol  . Despite its potential, quipazine was never fully developed for clinical use.

• Starting Materials: The primary reactants are 2-chloroquinoline and piperazine.
• Reaction Conditions: The reaction typically requires appropriate solvents and conditions that facilitate nucleophilic substitution.
• Purification: The product is purified through standard organic chemistry techniques such as recrystallization or chromatography  .

Quipazine exhibits a range of biological activities, primarily as a serotonin reuptake inhibitor and a nonselective agonist at several serotonin receptors. It has been shown to produce significant effects in animal models, including:

• Psychedelic-like Effects: Quipazine induces head-twitch responses and other behaviors consistent with psychedelic activity in rodents and primates  .
• Serotonin Receptor Binding: It binds effectively to 5-HT2A and 5-HT3 receptors, influencing various physiological responses such as smooth muscle contraction and neurotransmitter release  .

While quipazine has demonstrated robust activity in preclinical studies, it failed to produce psychedelic effects in humans at doses up to 25 mg due to side effects associated with 5-HT3 receptor activation .

Quipazine’s applications are primarily confined to research settings:

• Neuroscience Research: It is used to study serotonin receptor dynamics and the mechanisms underlying psychedelic effects.
• Pharmacological Studies: Quipazine serves as a tool for exploring serotonin-related pathways and potential therapeutic targets for mood disorders  .

Research has elucidated quipazine’s interactions with various serotonin receptors:

• 5-HT2A Receptor: Quipazine acts as an agonist, promoting signaling pathways associated with this receptor type. Studies indicate that it enhances inositol monophosphate accumulation, similar to classic psychedelics like 2,5-dimethoxy-4-iodoamphetamine (DOI)  .
• Comparative Activity: Quipazine’s activity profile has been compared to other serotonergic compounds, revealing unique binding characteristics and effects on behavior in animal models  .

Quipazine shares structural similarities with several other compounds within the piperazine class. Here are some notable comparisons:

Quipazine’s unique structure allows it to interact specifically with serotonin receptors while exhibiting a distinct pharmacological profile compared to these similar compounds. Its ability to act as both an agonist and a reuptake inhibitor sets it apart within the realm of serotonergic agents.

Psychedelic-like Properties of Quipazine and Its Structural Analogues in Mice

Mario de la Fuente Revenga, Urjita H Shah, Nima Nassehi, Alaina M Jaster, Prithvi Hemanth, Salvador Sierra, Malgorzata Dukat, Javier González-Maeso
PMID: 33400504   DOI: 10.1021/acschemneuro.0c00291

Abstract

Known classic psychedelic serotonin 2A receptor (5-HT
R) agonists retain a tryptamine or phenethylamine at their structural core. However, activation of the 5-HT
R can be elicited by drugs lacking these fundamental scaffolds. Such is the case of the N-substituted piperazine quipazine. Here, we show that quipazine bound to and activated 5-HT
R as measured by [
H]ketanserin binding displacement, Ca
mobilization, and accumulation of the canonical G
signaling pathway mediator inositol monophosphate (IP
)
and
. Additionally, quipazine induced via 5-HT
R an expression pattern of immediate early genes (IEG) in the mouse somatosensory cortex consistent with that of classic psychedelics. In the mouse head-twitch response (HTR) model of psychedelic-like action, quipazine produced a lasting effect with high maximal responses during the peak effect that were successfully blocked by the 5-HT
R antagonist M100907 and absent in 5-HT
R knockout (KO) mice. The acute effect of quipazine on HTR appeared to be unaffected by serotonin depletion and was independent from 5-HT
R activation. Interestingly, some of these features were shared by its deaza bioisostere 2-NP, but not by other closely related piperazine congeners, suggesting that quipazine might represent a distinct cluster within the family of psychoactive piperazines. Together, our results add to the mounting evidence that quipazine’s profile matches that of classic psychedelic 5-HT
R agonists at cellular signaling and behavioral pharmacology levels.

Stimulation of 5-HT2A receptors recovers sensory responsiveness in acute spinal neonatal rats

Hillary E Swann, Sierra D Kauer, Jacob T Allmond, Michele R Brumley
PMID: 28004950   DOI: 10.1037/bne0000176

Abstract

Quipazine is a 5-HT
-receptor agonist that has been used to induce motor activity and promote recovery of function after spinal cord injury in neonatal and adult rodents. Sensory stimulation also activates sensory and motor circuits and promotes recovery after spinal cord injury. In rats, tail pinching is an effective and robust method of sacrocaudal sensory afferent stimulation that induces motor activity, including alternating stepping. In this study, responsiveness to a tail pinch following treatment with quipazine (or saline vehicle control) was examined in spinal cord transected (at midthoracic level) and intact neonatal rats. Rat pups were secured in the supine posture with limbs unrestricted. Quipazine or saline was administered intraperitoneally and after a 10-min period, a tail pinch was administered. A 1-min baseline period prior to tail-pinch administration and a 1-min response period postpinch was observed and hind-limb motor activity, including locomotor-like stepping behavior, was recorded and analyzed. Neonatal rats showed an immediate and robust response to sensory stimulation induced by the tail pinch. Quipazine recovered hind-limb movement and step frequency in spinal rats back to intact levels, suggesting a synergistic, additive effect of 5-HT-receptor and sensory stimulation in spinal rats. Although levels of activity in spinal rats were restored with quipazine, movement quality (high vs. low amplitude) was only partially restored. (PsycINFO Database Record

Cortico-reticulo-spinal circuit reorganization enables functional recovery after severe spinal cord contusion

Leonie Asboth, Lucia Friedli, Janine Beauparlant, Cristina Martinez-Gonzalez, Selin Anil, Elodie Rey, Laetitia Baud, Galyna Pidpruzhnykova, Mark A Anderson, Polina Shkorbatova, Laura Batti, Stephane Pagès, Julie Kreider, Bernard L Schneider, Quentin Barraud, Gregoire Courtine
PMID: 29556028   DOI: 10.1038/s41593-018-0093-5

Abstract

Severe spinal cord contusions interrupt nearly all brain projections to lumbar circuits producing leg movement. Failure of these projections to reorganize leads to permanent paralysis. Here we modeled these injuries in rodents. A severe contusion abolished all motor cortex projections below injury. However, the motor cortex immediately regained adaptive control over the paralyzed legs during electrochemical neuromodulation of lumbar circuits. Glutamatergic reticulospinal neurons with residual projections below the injury relayed the cortical command downstream. Gravity-assisted rehabilitation enabled by the neuromodulation therapy reinforced these reticulospinal projections, rerouting cortical information through this pathway. This circuit reorganization mediated a motor cortex-dependent recovery of natural walking and swimming without requiring neuromodulation. Cortico-reticulo-spinal circuit reorganization may also improve recovery in humans.

Quipazine Elicits Swallowing in the Arterially Perfused Rat Preparation: A Role for Medullary Raphe Nuclei?

Victor Bergé-Laval, Christian Gestreau
PMID: 32698469   DOI: 10.3390/ijms21145120