5-HT1F Receptor ( Ki = 1.6 nM )
Serotonin 5-HT1F receptor agonist (Ki = 1.6 nM) [1]

LY334370 does not exhibit vasoconstrictor effects on human cerebral arteries in vitro, unless it is administered at a dose of 10-5 M, at which point it causes an 8.5±5.7% contraction, which is not statistically significant[1].

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In isolated human cerebral arteries from the temporal-parietal region, LY334370 (up to 10^-5 M) did not produce a significant vasoconstrictor effect. At 10^-5 M, it caused only 8.5 ± 5.7% contraction relative to the maximum KCl-induced contraction, which was not statistically significant. In contrast, sumatriptan potently constricted the same vessels with an Emax of 50 ± 10% and a pD2 of 6.8 ± 0.2. [1]

Intravenous LY334370 administration at 3 mg/kg (n = 3) or 10 mg/kg (n = 6) causes an increase in dural blood vessel diameter of 135±6% and 106±11%, respectively, after electrical stimulation; these values do not differ significantly from the corresponding control values. Since dural blood vessel diameter is actually 43±4 arbitrary units before drug injection and 43±4 arbitrary units 15 minutes after injection of LY334370 (10 mg/kg), LY334370 has no effect on dural blood vessel diameter per se[1].

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Neurogenic Dural Vasodilation in Rats: Intravenous administration of LY334370 at 3 mg/kg or 10 mg/kg had no significant effect on the neurogenic vasodilation of dural blood vessels evoked by electrical stimulation of the dura mater in anesthetized rats. The compound also had no effect on baseline dural vessel diameter. [1]
Trigeminal Neuronal Responses in Rats: Intravenous LY334370 (0.3, 1, and 3 mg/kg) produced a significant and dose-dependent inhibition of the evoked responses of second-order neurons in the trigeminal nucleus caudalis to electrical stimulation of the dura mater in anesthetized rats. The inhibition reached a maximum of -64 ± 14% from control at 19 ± 3 minutes after the 3 mg/kg dose. [1]
Carrageenan-induced Hyperalgesia in Rats: Intravenous administration of LY334370 at 3 mg/kg had no effect on the mechanical hyperalgesia induced by carrageenan injection into the rat paw. In the same assay, morphine (1-3 mg/kg, sc) completely reversed the hyperalgesia in a dose-dependent manner. [1]
Nociceptive Reflexes in Rabbits: Intravenous LY334370 (0.3 - 3 mg/kg) had no significant effect on baseline, facilitated, or wind-up nociceptive reflex responses in spinalized, decerebrate rabbits. [1]

n this study, human cerebral arteries are used. Segments are prepared as previously described, but briefly they are placed in a buffer solution containing (mM) NaCl 119, NaHCo3 15, KCl 4.6, CaCl2 1.5, NaH2PO4 1.2, MgCl2 1.2, and glucose 5.5. Sections of the vessel, measuring 0.5 mm in diameter and 1 to 2 mm in length, are placed in a tissue bath that is heated to 37°C and contains a buffer solution that has been agitated with 5% CO2 and 95% O2. Four mN of tension is applied to the vessel segments, and they are left to stabilize there for one to one and a half hours. Exposure to 60 mM KCl is used to test the reactivity of vessels. Only if the response is similar to the segment used for LY334370 testing is this repeated twice for each segment. As a percentage of the maximum KC1 response, responses to LY334370 are computed[1].

There are 300–400 g male Sprague-Dawley rats used. Intravital microscopy and a video dimension analyzer are used to measure the diameter of a branch of the middle meningeal artery in the intact skull of rats housed in a stereotaxic frame after their skulls have been thinned and exposed through drilling. A bipolar stimulating electrode, positioned on the cranial window surface about 200 μM away from the vessel of interest, is used to induce neurogenic vasodilation. After LY334370 (3 or 10 mg/kg, iv.) is administered five minutes after an electrical stimulation response that produces a control vasodilation is produced, and after another fifteen minutes, the electrical stimulation is repeated. For each response, the mean maximum percentage increase in dural vessel diameter relative to the pre-stimulus baseline is calculated. Analysis of variance is then used to compare the vasodilation responses evoked in the presence or absence of LY334370, and paired t-tests are employed to make these comparisons[1].

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Human Cerebral Artery Study: Human cerebral artery segments (0.5 mm diameter, 1-2 mm length) from the temporal-parietal region were mounted in a temperature-controlled tissue bath (37°C) with oxygenated buffer. They were placed under 4 mN tension and stabilized. Reactivity was tested with 60 mM KCl. Cumulative concentration-response curves to LY334370 or sumatriptan were constructed, with responses calculated as a percentage of the maximum KCl contraction. [1]
Neurogenic Dural Vasodilation Study in Rats: Male Sprague-Dawley rats (300-400 g) were anesthetized with pentobarbitone sodium. A branch of the middle meningeal artery was visualized through a thinned skull, and its diameter was measured using intravital microscopy. Neurogenic vasodilation was evoked by electrical stimulation (5 Hz, 1 ms, 50-300 μA for 10 sec) via an electrode placed on the cranial window. After a control response, LY334370 (3 or 10 mg/kg) or vehicle was administered intravenously, and the stimulation was repeated 15 minutes later. [1]
Trigeminal Neuronal Response Study in Rats: Male Sprague-Dawley rats (320-420 g) were anesthetized with halothane and maintained on sodium pentobarbitone infusion. Single-unit extracellular recordings were made from neurons in the caudal trigeminal nucleus. Neuronal responses were evoked by electrical stimulation (100-200 μs, 1-3 mA, 1 Hz for 20 sec) of the middle meningeal artery, repeated every 200 sec. LY334370 was administered intravenously in cumulative doses (0.3, 1, 3 mg/kg) at 10-minute intervals. [1]
Rat Carrageenan-induced Hyperalgesia Study: Male Sprague-Dawley rats (100-120 g) had their baseline paw pressure vocalization threshold determined. Carrageenan (4.5 mg in 0.15 ml) was injected into one hind paw. Two hours later, rats received either morphine (0.1-3.0 mg/kg, sc), morphine vehicle (saline), LY334370 (3 mg/kg, iv), or LY334370 vehicle (distilled water). Vocalization thresholds were re-determined 1 hour after drug/vehicle administration. [1]
Rabbit Nociceptive Reflex Study: New Zealand White rabbits (2.5-3.5 kg) were anesthetized, spinalized at C2, and decerebrated. Motor unit activity was recorded from the hindlimb. Baseline responses to single electrical shocks (1 ms, 2x threshold voltage) and facilitated/wind-up responses to a 20-shock conditioning stimulus (1 Hz) were recorded. LY334370 (0.3-3 mg/kg, iv) or vehicle was administered, and its effects on these reflex responses were evaluated. [1]

Phase I clinical studies have shown that LY334370 has good oral bioavailability, with a time to peak concentration (tmax) of 1 to 2 hours and an elimination half-life of approximately 15 hours. [1]

Phase I clinical trials showed that LY334370 was well tolerated at oral doses up to 400 mg. Reported side effects included fatigue, drowsiness, and dizziness. No cardiovascular adverse reactions were observed (assessed by blood pressure, pulse, or electrocardiogram). [1]

[1]. Cephalalgia. 1999 Dec;19(10):851-8.

This study aimed to investigate whether the selective 5-HT1F receptor agonist LY334370, besides inhibiting dural plasma exudation, possesses other possible anti-migraine mechanisms. In vitro experiments showed that LY334370 (at concentrations up to 10⁻⁵ M) had no vasoconstrictive effect on human cerebral arteries. In anesthetized rats, LY334370 (intravenous injection, up to 10 mg/kg) had no effect on neurogenic vasodilation induced by electrical stimulation of the dura mater. Furthermore, LY334370 (intravenous injection, up to 3 mg/kg) had no effect on hyperalgesia induced by carrageenan injection in the paws of conscious rats or on nociceptive reflexes in decerebrated rabbits, indicating that it does not possess systemic analgesic effects. However, in anesthetized rats, intravenous injection of LY334370 at a dose of 3 mg kg⁻¹ significantly inhibited the activation of second-order neurons in the trigeminal caudate nucleus induced by electrical stimulation of the dura mater. These results suggest that LY334370 has a central mechanism of action that blocks the transmission of nociceptive impulses in the caudate nucleus of the trigeminal nerve, which may be one of the mechanisms by which it exerts its anti-migraine effect. [1] LY334370 (4-fluoro-N-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]-benzamide) is a potent and selective 5-HT1F receptor agonist that has been developed as an anti-migraine drug. It is about 100 times more selective for 5-HT1B and 5-HT1D receptors than for 5-HT1F receptors. [1] The anti-migraine mechanism of LY334370 is thought to exert its central effect by blocking the transmission of nociceptive impulses in the caudate nucleus of the trigeminal nerve, rather than by intracranial vasoconstriction or inhibition of neurogenic dural vasodilation. It does not appear to have a systemic analgesic effect. [1] Preliminary Phase II clinical data showed that, compared with placebo, oral administration of 80 mg and 200 mg of LY334370 significantly relieved pain in patients with moderate to severe migraines within 2 hours. [1]

C21H23CLFN3O

387.878227472305

387.151

C, 65.03; H, 5.98; Cl, 9.14; F, 4.90; N, 10.83; O, 4.12

199673-74-0

199673-74-0(LY 334370 hydrochloride);182563-08-2 (LY 334370 Free Base);

19710026

Typically exists as solid at room temperature

5.181

3

3

3

27

486

0

C(NC1C=CC2=C(C=1)C(C1CCN(C)CC1)=CN2)(=O)C1=CC=C(F)C=C1.[H]Cl

DGPDGAPZTPSHBL-UHFFFAOYSA-N

InChI=1S/C21H22FN3O.ClH/c1-25-10-8-14(9-11-25)19-13-23-20-7-6-17(12-18(19)20)24-21(26)15-2-4-16(22)5-3-15;/h2-7,12-14,23H,8-11H2,1H3,(H,24,26);1H

4-Fluoro-N-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]benzamide hydrochloride

LY 334370; LY-334370; LY334370; LY 334370 hydrochloride; 199673-74-0; LY334370 (hydrochloride); 4-Fluoro-N-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]benzamide hydrochloride; 4-fluoro-N-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]benzamidehydrochloride; BenzaMide, 4-fluoro-N-[3-(1-Methyl-4-piperidinyl)-1H-indol-5-yl]-, Monohydrochloride; 4-fluoro-N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]benzamide;hydrochloride; SCHEMBL8604274; LY 334370 hydrochloride; LY 334370 HCl.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)