5-HT_1F Receptor ( Ki = 1.6 nM )
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].

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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LY334370 (up to 10^-5 M) had no significant vasoconstrictor effect on human isolated cerebral arteries. In contrast, sumatriptan produced potent contraction (Emax ~50%, pD2 ~6.8) over the same concentration range. [1]
Autoradiographic studies using [³H]LY334370 localized 5HT_1F receptor binding sites in the trigeminal nucleus caudalis of rats and guinea pigs. [1]
In situ hybridization in guinea pigs demonstrated 5HT_1F receptor mRNA in cell bodies of the trigeminal ganglion. [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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In anesthetized rats, intravenous administration of LY334370 (3 mg kg⁻¹ and 10 mg kg⁻¹) had no effect on neurogenic vasodilation of dural blood vessels evoked by electrical stimulation of the dura mater. [1]
In anesthetized rats, LY334370 (0.3, 1, and 3 mg kg⁻¹, i.v.) produced a significant, dose-dependent inhibition of evoked responses in second-order neurons within the trigeminal nucleus caudalis following electrical stimulation of the dura mater. Maximum inhibition (64 ± 14%) was observed 19 ± 3 min after the 3 mg kg⁻¹ dose. [1]
In conscious rats, LY334370 (3 mg kg⁻¹, i.v.) had no effect on carrageenan-induced mechanical hyperalgesia, whereas morphine (1-3 mg kg⁻¹, s.c.) dose-dependently reversed it. [1]
In spinalized, decerebrate rabbits, LY334370 (0.3-3 mg kg⁻¹, i.v.) had no significant effect on baseline, facilitated, or wind-up nociceptive reflex responses. [1]
Oral administration of LY334370 (1-100 µg kg⁻¹) in rats inhibited c-fos expression in the trigeminal nucleus caudalis induced by electrical stimulation of the trigeminal ganglion. [1]

In 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: Segments of human cerebral artery (temporal-parietal region) were obtained from neurosurgery. Vessels were placed in a physiological buffer solution, mounted in a tissue bath at 37°C, and given a tension of 4 mN. Reactivity was tested with 60 mM KCl. Cumulative concentration-response curves to agonists were constructed. Responses were calculated as a percentage of the maximum KCl-induced contraction. [1]
Neurogenic Dural Vasodilation Study in Rats: Male Sprague-Dawley rats 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 dura. After a control response, LY334370 (3 or 10 mg kg⁻¹, i.v.) was administered, and stimulation was repeated 15 min later. [1]
Trigeminal Neuronal Response Study in Rats: Male Sprague-Dawley rats were anesthetized with halothane and maintained with pentobarbitone infusion. The brainstem was exposed. Single-unit extracellular recordings were made from neurons in the caudal trigeminal nucleus. Neuronal activity was evoked by electrical stimulation of the middle meningeal artery (1-3 mA, 1 Hz for 20 sec) repeated every 200 sec. LY334370 was administered i.v. in cumulative doses (0.3, 1, 3 mg kg⁻¹) at 10-min intervals. [1]
Carrageenan-induced Hyperalgesia Study in Rats: The paw pressure vocalization threshold was determined in conscious rats using an algesiometer. Carrageenan was injected into one hind paw to induce inflammation and hyperalgesia. Two hours later, rats received either morphine (s.c.), LY334370 (3 mg kg⁻¹, i.v.), or respective vehicles. Vocalization thresholds were re-determined 1 hour after drug administration. [1]
Nociceptive Reflex Study in Rabbits: Male New Zealand White rabbits were anesthetized, spinalized at C2, and decerebrated. Electrical stimuli were applied to a hind limb receptive field. Single shocks were delivered to establish a baseline. A conditioning stimulus (20 shocks at 1 Hz) was applied at 15-min intervals to evoke wind-up and facilitation. After vehicle administration, cumulative doses of LY334370 (0.3, 1, 3 mg kg⁻¹, i.v.) were given at 15-min intervals prior to conditioning stimuli. [1]

Phase I studies have shown that oral administration of LY334370 is well tolerated at doses up to 400 mg. It has good oral bioavailability, with a time to peak concentration (Tmax) of 1 to 2 hours and an elimination half-life of 15 hours. [1]

In the Phase I study, side effects of LY334370 included weakness, drowsiness, and dizziness. No cardiovascular effects were observed (assessed by blood pressure, pulse, or electrocardiogram) at doses up to 400 mg. [1]

[1]. Possible antimigraine mechanisms of action of the 5HT1F receptor agonist LY334370. 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 (concentrations up to 10⁻⁵ M) had no vasoconstrictive effect on human cerebral arteries. In anesthetized rats, LY334370 (intravenous injection, doses up to 10 mg/kg) had no effect on neurogenic vasodilation induced by electrical stimulation of the dura mater. Furthermore, LY334370 (intravenous injection, doses 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 the mechanism of action of LY334370 may be to block the transmission of nociceptive impulses in the trigeminal caudate nucleus, which may be one of the mechanisms by which it exerts its anti-migraine effect. [1] LY334370 is a potent and selective 5-HT₁F receptor agonist and its application in the acute treatment of migraine is currently under investigation. [1] Preliminary Phase II clinical trial data showed that oral administration of 80 mg and 200 mg of LY334370 significantly relieved pain in patients with moderate to severe migraine within 2 hours compared with placebo. [1] The anti-migraine mechanism of LY334370 is believed to be the inhibition of nociceptive transmission in the trigeminal caudate nucleus, rather than through intracranial vasoconstriction, inhibition of neurogenic dural vasodilation, or general analgesia. [1] In animal models, LY334370 effectively inhibited neurogenic dural plasma exudation (ED₅₀ = 20 µg kg⁻¹ in rats), an effect attributed to the activation of 5-HT₁F receptors. [1]

C21H22FN3O

351.41728

351.17

182563-08-2

199673-74-0(LY334370 hydrochloride)

5311258

White to off-white solid powder

504.1ºC at 760 mmHg

258.7ºC

5.181

2

3

3

26

486

0

O=C(C1=CC=C(F)C=C1)NC2=CC3=C(C=C2)NC=C3C4CCN(C)CC4

MDMJLMDBRQXOOI-UHFFFAOYSA-N

InChI=1S/C21H22FN3O/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)

4-fluoro-N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]benzamide

182563-08-2; LY 334370; 4-fluoro-N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]benzamide; LY-334370; 5Q7I1WL2UY; CHEMBL101690; 4-Fluoro-N-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)benzamide; LY334370

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

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

DMSO: ≥ 55.5 mg/mL (~157.9 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.11 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.11 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.11 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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