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Repinotan (BAYx3702), an aminomethylchroman derivative, is a selective 5-HT1A receptor full agonist with high potency and efficacy. It has neuroprotective effects in animal studies, and was trialed in humans for reducing brain injury following head trauma. It was subsequently trialed up to phase II for treatment of stroke, but while side effects were mild and consisted mainly of nausea, repinotan failed to demonstrate sufficient efficacy to justify further clinical trials. However, repinotan continues to be investigated for other applications, and was found to be effective at counteracting the respiratory depression produced by morphine, though with slight reduction in analgesic effects.

Brief History
also predicted peak sales of 450 million Euros. The company expected to launch repinotan throughout Europe and the US in 2006. However, the drug continues to be under investigation for different clinical treatments other than its original intent.

References

See Also

Repinotan was made by Bayer Healthcare AG (Wuppertal, Germany) during the early 2000s. It was originally trialed for reducing brain injury following head trauma, but was found to be ineffective. Instead, it was investigated for other applications and found to be effective at counteracting respiratory depression produced by morphine.

Chemical Structure and Synthesis
Repinotan was originally synthesized by Bayer Healthcare AG (Wuppertal, Germany). It is an enantiomerically pure aminomethyl chromane derivative with a saccharinylbutyl substituent. A metabolically stable 14carbon-label in the chromane moiety was required for studies of repinotan’s pharmacokinetics. The 14carbon labeled metabolite M-6 of repinotan was synthesized as the hydrochloride and hydroxylated in the 6-position of the chromane moiety. [14C]-phenol was used as the starting compound. It was used for the known preparation of chromane rings via Michael adduct formation in the first labeling synthesis. The second labeling route was started from commercially available [carbonyl-14C]-2-hydroxy-acetophenone. The deacetylation and the debenzylation steps were carried out using HCI, Pd/C in the first and H2, Pd/C in the second step. The desired product was obtained after purification by semi-preparative HPLC in good quality.

Mechanism of Action
Repinotan hydrochloride (BAYx3702) is a highly selective 5-HT1A receptor full agonist. It is blocked by the specific 5-HT1A receptor antagonist, WAY 1006345 and its primary metabolizer is CYP2D6. CYP2D6 is known to be subject to ethnic differences and believed to act by neuronal hyperpolarization.

When repinotan first binds to both pre- and post-synaptic 5-HT1A receptors, G protein-coupled inwardly rectifying K+ channels are activated. This causes hyperpolarization. Because hyperpolarization results in the inhibition of neuron firing and the reduction of glutamate release, these mechanisms could explain the neuroprotective efficacy of repinotan by leading to protection of neurons against overexcitation.

In addition, repinotan affects the death-inhibiting protein Bcl-2, the serotonergic glial growth factor S-100beta, and Nerve Growth Factor. It also suppresses the activity of caspase-3 through MAPK and PKCalpha, and blocks apoptosis caused by anoxia/reoxygenation and H(2)O(2) treatment.

Repinotan has been found to bind with relatively high to moderate affinity to the receptors alpha-1 and alpha-2 adrenergic, 5-HT7- and 5-HT1D, dopamine D2 and D4, sigma sites, and 5-HT2C. It is able to increase the activity of dopaminergic neurons in the ventral segmental area (VTA) as well as dopamine release into the VTA and medial prefrontal cortex. It has been suggested that repinotan may modulate the activity of VTA dopaminergic neurons. This may be done through a change in the pyramidal output of medial prefrontal cortex neurons projecting to the VTA.

Pharmacodynamics
Repinotan hydrochloride acts as a selective high-affinity full receptor agonist at the 5-HT1A receptor subtype. 5-HT1A receptor agonists act by increasing the activity of dopamine (DA) neurons in the ventral segmental area as well as DA release in the medial prefrontal cortex (a 5-HT1A receptor-rich area).

Additionally, it is an extremely potent drug, which is able to effectively cross the blood-brain barrier. The distribution equilibrium between plasma and brain is reached almost immediately after the start of infusion and the drug is highly potent.

Repinotan’s efficacy is mainly dependent on factors such as the delay between the onset of stroke symptoms and the start of repinotan. The age and blood pressure of the patient also play a role. Decreases in response with increasing age and decreases in response as blood pressure increases are generally observed. The most efficient dose of repinotan is approximately 1.25 mg/dose.

Pharmacokinetics
Repinotan’s primary route of administration is by intravenous injection, which indicates that it goes directly into the bloodstream. It is able to cross the blood-brain barrier- a highly selective permeability barrier that separates the circulating blood from the extracellular fluid of the brain in the central nervous system. Repinotan crosses freely in both directions with diffusion as the driving force. In addition, it is uncharged, which is consistent with the fact that it able to pass the lipophilic and non-polar blood-brain barrier.

The half-life of repinotan is approximately 1 hour. Elimination occurs in parallel from plasma and brain and its volume of distribution at steady-state and plasma clearance is independent of dose. This is indicative of linear pharmacokinetics and dose-proportionality over the dose range of 0.1-3.0 micrograms/kg/h.

Repinotan is well-tolerated at infusion rates of up to 150 microg/h. The optimum dose of repinotan is approximately 5 to 20 micrograms/L in plasma and it has been shown to have neuroprotective effects when given at the frequency of 0.3-100 micrograms/kg/h. 1.25 mg/day is the optimal dose.

Potential Effects of Gender, Age, and Interethnic Differences on Repinotan Administration
CYP2D6, the primary metabolizer of repinotan, has been found to be subject to polymorphism and ethnic differences. Gender and age were shown to have no influence on repinotan’s pharmacokinetics. Bodyweight also did not have a major influence.

Treatment
=== Acute Ischemic Stroke ===

Repinotan was originally developed by Bayer Healthcare AG (Wuppertal, Germany) as an oral treatment for depression. However, it was instead trialed as a candidate for reducing brain injury following head trauma. The drug was established in rodent model preclinical studies as a preventative of secondary brain damage in brain-injured patients suffering from acute ischemic stroke. Early trials showed repinotan’s ability to reduce hippocampal CA1 and CA3 neuronal loss and cortical tissue damage. It was also shown to attenuate spatial learning deficits following controlled cortical impact injury. However, trials were discontinued, as repinotan’s efficacy was not demonstrated to be sufficient.

Respiratory Depression Antagonization

Currently, repinotan has been found to be effective at antagonizing morphine-induced ventilatory depression. At small doses it has pronociceptive effects and has been found to prolong anitonociception (reduced sensitivity to painful stimuli). However, it has not been found to depress nociception itself. It suppresses nociception at higher doses, but enhances nociception at smaller doses. Repinotan may be applicable to Parkinson’s, as it is able to reduce glutamate-induced excitotoxicity and excitoxicity-mediated cell death.

Additional Medications Trialed
Another stroke medication trialed at the same time, piclozotan, is similar to repinotan in that it is a serotonin agonist, which also interferes with the ischemic cascade. Other drugs included zonampanel, which acts as an AMPA receptor antagonist instead of a 5-HT1A receptor agonist and DP-b99. DP-B99 is a metal iron chelator. These drugs were found to act even worse as stroke medications than repinotan and trials were discontinued.

Side Effects
Repinotan’s side effects during trials as a preventative of secondary brain damage in brain-injured patients suffering from acute ischemic stroke consisted mainly of serotonergic side effects such as nausea and vomiting. The most common side effect was headache. The most common severe adverse effects were neurological worsening, cerebral hemorrhagne, and brain edema. However, the general profile was determined to be safe and well-tolerated.

Its current investigation as an antagonist for morphine-induced depression of ventilation has shown there to be no serious cardiovascular side effects at an optimum dose of 20 micrograms/kg. However, a slight decrease in mean arterial blood pressure was a more minor effect. Repinotan concentration has been correlated with a reduction in pupil diameter.

Original Predictions and Current Availability
Currently, repinotan is not commercially available in the United States. Lehman Brothers originally predicted a launch date of 2006 in March 2002 and estimated peak sales of $1000 million in the U.S. alone. A 20 to 30% probability of the drug reaching market was also anticipated. Bank Vontobel estimated a launch date of 2006 as well with potential sales of 450 million Euros in its fifth year of sales. Bayer also predicted peak sales of 450 million Euros. The company expected to launch repinotan throughout Europe and the US in 2006. However, the drug continues to be under investigation for different clinical treatments other than its original intent.