Besipirdine

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Chemical compound

title: "Besipirdine" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public tags: ["nootropics", "4-pyridyl-compounds"] description: "Chemical compound" topic_path: "general/nootropics" source: "https://en.wikipedia.org/wiki/Besipirdine" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0

::summary Chemical compound ::

| tradename = | pregnancy_category = | legal_status = Unscheduled | routes_of_administration =

| bioavailability = | metabolism = | excretion =

| C=16 | H=17 | N=3 | smiles = CCCN(C1=CC=NC=C1)N2C=CC3=CC=CC=C32

Besipirdine (besipirdine hydrochloride, or HP749), an indole-substituted analog of 4-aminopyridine, is a nootropic drug developed for the treatment of Alzheimer's disease (AD).

History

Besipirdine was first considered for the treatment of obsessive-compulsive disorder (OCD). Hoechst-Roussel Pharmaceuticals, Inc. (Hoecst AG) filed a patent in July 1993 protecting the use of N-(pyridinyl)-1H-indol-1-amines, including besipirdine, for the treatment of OCD, supported by preliminary data gathered from rat studies . In 1995, Hoechst AG filed a patent protecting the production of besipirdine, this time describing its memory-enhancing, analgetic and antidepressant qualities . With increasing research on besipirdine uncovering its effects on the cholinergic system, Hoechst AG filed a patent in the following year to protect substituted n-(pyrrol-1-yl)pyridinamines as anticonvulsant agents |country=WO |number=1997004777 A1 |status= application |title=Use off unsubstituted and substituted n-(pyrrol-1-yl)pyridinamines as anticonvulsant agents |pubdate=1997-02-13 |fdate=1996-07-08 |pridate=1995-07-27 |invent1= Huger FP, Kongasamut S, Smith CP, Tang L |assign1= Hoechst Marion Roussel Inc |country=WO |number=2005035496 A1 |status= application |title=Process for the preparation of n-amino substituted heterocyclic compounds |pubdate=2005-04-21 |fdate=2004-10-01 |pridate=2003-10-03 |invent1= Dubberke S, Hanna RD, Lee GE, Mueller-Lehar J, Utz R, Weiberth F |assign1= Aventis Pharma Inc |country=WO |number=2007096777 A2 |status= application |title=Crystal form of besipirdine chlorhydrate, process preparation and use thereof |pubdate=2007-08-30 |fdate=2007-02-20 |pridate=2007-02-30 |invent1= Bienayme H, Ferte J |assign1= Urogene

Mechanism of action

As a member of the aminopyridine class, besipirdine enhances the release of acetylcholine by blocking M-channels, voltage-gated K+ channels, increasing neuronal excitation by depolarizing the cell. Additionally, besipirdine antagonizes the noradrenergic α2 receptor, increasing electrically-stimulated and spontaneous [3H]norepinephrine release from cortical tissue slices, and inhibits norepinephrine uptake. The exact pathway is not yet understood but it has been shown that besipirdine does not open sodium channels, so its consequential effect on norephinephrine release may be Ca2+-independent. Further, [3H]norepinephrine release seems to be dependent on frequency and concentration of besipirdine in that higher frequency of stimulation causes a concentration-dependent inhibition of voltage-dependent K+ channels, which leads to inhibition of norepinephrine release.

Medical uses

Alzheimer's disease

The most successful treatments for AD have been strategies targeting the cholinergic activity in the central nervous system, like acetylcholinesterase inhibitors. Other treatments target the adrenergic system and have been shown to improve memory deficits associated with AD. It was hypothesized that simultaneous treatment for both cholinergic and adrenergic deficits would be more effective than treatment that targeted individual systems alone. Besipirdine was shown to target dysfunctional cholinergic and adrenergic systems in Alzheimer's disease. It has been suggested as an anticonvulsant because of its adrenergic effects. Its effects on the cholinergic system may improve memory and cognitive deficits symptomatic of AD.

Other

Besipirdine was originally suggested as a treatment for OCD due to its effects on the adrenergic and serotonergic systems. "In vitro" studies of besipirdine indicated its potency in inhibiting serotonin reuptake in addition to norepinephrine reuptake. "In vivo", besipirdine showed efficacy in reducing schedule-induced polydipsia (SIP) in rats. The drug's anticonvulsant properties ultimately led Hoechst AG to pursue it as a treatment for Alzheimer's disease. After its discontinuation in the mid-1990s, besipirdine was re-evaluated as an oral treatment for Over Active Bladder (OAB) and is currently undergoing Phase III clinical trials, under UroGene. Interest in besipirdine as a treatment for OAB was piqued by its known effects on the adrenergic system. In isolated studies, besipirdine showed greater potency than duloxetine on bladder capacity, micturition volume, intercontraction interval, and an increase in striated sphincter EMG activity.

Pharmacology

Besipirdine primarily acts to enhance both cholinergic and adrenergic neurotransmission in the central nervous system. It is administered orally at a maximum tolerated dose (MTD) of 50 mg BID. In Phase II clinical trials, patients were administered 5 mg or 20 mg BID doses of besipirdine. Its N-despropyl metabolite, P86-7480, exhibits transient vasoconstrictor effects, producing a pressor effect of 16 ± 4 mm Hg after intravenous administration of 0.1 mg/kg, in monkey, rat and dog models.

Pharmacokinetics

The pharmacokinetics of besipirdine have been studied in conscious monkey. The calculated elimination half-life (t1/2) of besipirdine and P86-7480 after oral administration of 10, 20, and 40 mg/kg doses is 7.4 ± 2.1 hours. The t1/2 after intravenous administration of 10 mg/kg is 1.5 hours. Besipirdine is cleared through the kidneys at 0.13 ± 0.04 mL/min/kg; only 1% of the administered dose is excreted unused via the kidneys. In humans, using doses up to 30 mg, the t1/2 of besipirdine and P86-7480 were calculated as 3 hours, and 5.5–7 hours, respectively. Peak plasma concentrations of besipirdine and P86-7480 were calculated as 1.5–2 hours, and 2–3 hours, respectively.

Adverse effects

Besipirdine is reported to be well tolerated. More severe adverse effects, such as bradycardia and postural hypotension, may have been a result of a high ratio of adrenergic to cholinergic potency caused by the metabolite P86-7480, which has direct vasoconstrictor effects. Some studies suggest that the effects of besipirdine on cognition are reversible after withdrawal from treatment, indicating that the efficacy of the drug is primarily symptomatic and not neuroprotective.

General

Nausea and vomiting
Dry mouth
Headache
Rash
Eye disorder
Urinary frequency
Mouth ulceration
Loss of appetite
Dizziness
Paresthesia
General pain

Cardiovascular

Bradycardia
Postural hypotension
Premature ventricular contractions
Angina
Arrhythmia

Gastrointestinal

Gastrointestinal disorder
Flatulence
Constipation

Sleep

Insomnia
Somnolence

Psychological

Mood changes
Agitation
Nervousness

References

(1996). "A treatment and withdrawal trial of besipirdine in Alzheimer disease". Alzheimer Disease and Associated Disorders.
(December 1991). "Determination of HP 749, a potential therapeutic agent for Alzheimer's disease, in plasma by high-performance liquid chromatography". Journal of Chromatography.
(1995). "A "bridging" (safety/tolerance) study of besipirdine hydrochloride in patients with Alzheimer's disease". Life Sciences.
(July 1995). "The pharmacokinetics and cardiovascular pharmacodynamics of HP 749 (besipirdine HCl) and metabolite P86-7480 in the conscious monkey". Journal of Clinical Pharmacology.
(January 1996). "Synthesis and structure-activity relationships of N-propyl-N-(4-pyridinyl)-1H-indol-1-amine (besipirdine) and related analogs as potential therapeutic agents for Alzheimer's disease". Journal of Medicinal Chemistry.
(April 1996). "Frequency-dependent inhibition of neurotransmitter release by besipirdine and HP 184". European Journal of Pharmacology.
(February 1999). "The cholinergic hypothesis of Alzheimer's disease: a review of progress". Journal of Neurology, Neurosurgery, and Psychiatry.
(1991). "Lithium and hair loss in childhood". Psychosomatics.
(October 1994). "HP 749 enhances calcium-independent release of [3H]norepinephrine from rat cortical slices and synaptosomes". Neurochemical Research.
(November 1995). "Effects of besipirdine at the voltage-dependent sodium channel". British Journal of Pharmacology.
(1996). "Besipirdine (HP 749) reduces schedule-induced polydipsia in rats". Brain Research Bulletin.
(April 2008). "Schedule-induced polydipsia: a rat model of obsessive-compulsive disorder". Current Protocols in Neuroscience.
(2011). "Halothane-anesthetized rabbit: a new experimental model to test the effects of besipirdine and duloxetine on lower urinary tract function". Urologia Internationalis.
(April 2012). "Future Perspective in Pharmacological Treatment Options for Overactive Bladder Syndrome". European Urological Review.
(January 2006). "Effects of besipirdine on acetic acid-induced bladder irritation in rabbits. Comparison with duloxetine". Neurology and Urodynamics.
(1995). "Tolerability and pharmacodynamics of besipirdine in Alzheimer's disease". Biological Psychiatry.
(April 1997). "alpha-Adrenergic activity and cardiovascular effects of besipirdine HCl (HP 749) and metabolite P7480 in vitro and in the conscious rat and dog". The Journal of Pharmacology and Experimental Therapeutics.

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