5-HT1B Receptor (pKi = 9.4); 5-HT1D Receptor (pKi = 9.3)

Intracarotid infusions of capsaicin, alpha-CGRP and acetylcholine dose-dependently increased blood flow through the carotid artery. These responses remained unaffected after intravenous (i.v.) infusions of sumatriptan, PNU-142633, PNU-109291 or physiological saline; in contrast, donitriptan significantly attenuated the vasodilator responses to capsaicin, but not those to alpha-CGRP or acetylcholine. Only sumatriptan and donitriptan dose-dependently decreased the carotid blood flow. Interestingly, i.v. administration of the antagonist, SB224289 (5-HT(1B)), but not of BRL15572 (5-HT(1D)), abolished the inhibition by donitriptan. Conclusions and implications: The results suggest that the inhibition produced by donitriptan of capsaicin-induced external carotid vasodilatation is mainly mediated by 5-HT(1B), rather than 5-HT(1D), receptors, probably by a central mechanism [1].

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The aim of the present study was to determine whether donitriptan and sumatriptan decreased jugular venous oxygen saturation and increased carbon dioxide partial pressure in venous blood. However, previous studies conducted with these compounds cannot discriminate whether the decrease of venous oxygen saturation is dependent of cranial vasoconstrictor. In the present study, vehicle (n = 10), donitriptan (2.5, 10, and 40 microg/kg; n = 8) or sumatriptan (630 microg/kg; n = 8) were infused into the carotid artery in the anesthetized rat. Regional blood flows were evaluated in the presence of donitriptan (10 microg/kg; n = 6) or vehicle (n = 6). Jugular venous oxygen saturation was significantly decreased by donitriptan (from 10 microg/kg) with maximal changes of -32.9 +/- 8.0%. Jugular carbon dioxide partial pressure was increased by donitriptan, reaching maximal changes of 17.7 +/- 4.6% (P < 0.05 versus vehicle). Similarly, sumatriptan significantly decreased venous oxygen saturation and increased jugular carbon dioxide partial pressure. These changes induced by donitriptan are abolished by the 5-hydroxytryptamine (5-HT)(1B/1D) receptor antagonist GR 127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2-[-methyl-4(5-methyl-1,2,4)-oxadiazol-3-yl]-(1,1 biphenyl)-4-carboxamide dihydrochloride). In addition, donitriptan was devoid of significant effects on systemic arterial pressure, heart rate, or regional blood flows, including systemic arterial-jugular venous anastomotic, systemic, or cranial. The results demonstrate that donitriptan increases cerebral oxygen consumption by 5-HT(1B/1D) receptor activation in the absence of cranial vasoconstriction.[2]

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The effects of donitriptan on systemic arterial-jugular venous oxygen saturation difference were evaluated in pentobarbitone-anesthetized pigs. Oxygen and carbon dioxide partial pressures in systemic arterial and jugular venous blood as well as hemoglobin oxygen saturation were determined by conventional blood gas analysis. Vehicle (40% polyethyleneglycol in saline, n = 9) or donitriptan (0.01, 0.04, 0.16, 0.63, 2.5, 10, and 40 microg/kg, n = 7) were cumulatively infused over 15 min/dose. The involvement of 5-hydroxytryptamine(1B) (5-HT(1B)) receptors was assessed in the presence of the 5-HT(1B/1D) receptor antagonist, GR 127935. Donitriptan decreased markedly and dose dependently jugular venous oxygen saturation [ED(50) 0.5 (0.3-1.1) microg/kg], in parallel with increases in carotid vascular resistance [ED(50) 0.9 (0.7-1.1) microg/kg]. Since arterial oxygen saturation and partial pressure remained unchanged, donitriptan significantly increased arteriovenous oxygen saturation difference from 0.63 microg/kg (maximal variation: 57 +/- 18%, P < 0.05 compared with vehicle). Unexpectedly, donitriptan from 2.5 microg/kg induced marked and significant increases in carbon dioxide partial pressure (pVCO(2)) in venous blood (maximal increase 18.8 +/- 5.7%; P < 0.05 compared with vehicle). Pretreatment with GR 127935 (0.63 mg/kg, n = 5) abolished the fall in venous oxygen saturation and the increase in carotid vascular resistance and reduced the increases in pVCO(2) induced by donitriptan. The results demonstrate that donitriptan, via 5-HT(1B) receptor activation, decreases the oxygen saturation of venous blood draining the head, concomitantly with cranial vasoconstriction. Since donitriptan also increased pVCO(2), an effect upon cerebral oxygen consumption and metabolism is suggested in addition to cranial vasoconstriction, which may be relevant to its headache-relieving effects[3].

Experimental protocol [1]
After the animals (n=59) had been in a stable haemodynamic condition for at least 60 min, baseline values of mean blood pressure, heart rate and external carotid blood flow were determined. Subsequently, the animals were divided into four groups (n=20, 8, 20 and 11). [1]
The first group (n=20) was subdivided into five subgroups (n=4 each) that received consecutive 10-min i.v. infusions of, respectively: (i) sumatriptan (1, 3, 10, 30, 100 and 300 μg kg−1); (ii) donitriptan (0.1, 0.3, 1, 3, 10 and 30 μg kg−1); (iii) PNU-142633 (1, 3, 10, 30, 100 and 300 μg kg−1); (iv) PNU-109291 (0.3, 1, 3, 10, 30 and 100 μg kg−1); and (v) equivalent volumes of physiological saline (0.5 ml min−1 during 10 min; given six times). The above compounds were given consecutively following a cumulative dose-schedule as i.v. infusions (at a rate of 0.5 ml min−1 during 10 min for each dose). [1]
The second group (n=8) received consecutive intracarotid infusions (1 ml min−1, for 1 min) of capsaicin (10, 18, 30 and 56 μg min−1), α-CGRP (0.1, 0.3, 1 and 3 μg min−1) and acetylcholine (0.01, 0.03 and 0.1 μg min−1). Then, this group was subdivided into two subgroups (n=4 each) that received an intracarotid continuous infusion throughout the experiment of, respectively: (i) vehicle (0.3 ml min−1 of physiological saline); and (ii) phenylephrine (1.5 μg min−1, given at a rate of 0.3 ml min−1), which produced a carotid vasoconstriction similar to that elicited by the highest dose of sumatriptan (300 μg kg−1, i.v.) or donitriptan (30 μg kg−1, i.v.) (see first group for details). Twenty minutes after the start of the infusion of physiological saline or phenylephrine, the responses to the above doses of capsaicin, α-CGRP and acetylcholine (in this order) were elicited again as described above during the intracarotid continuous infusion of each compound. [1]
The third group (n=20) received a continuous intracarotid infusion of phenylephrine (1.5 μg min−1) as described previously and, 20 min later, the responses to the above doses of capsaicin, α-CGRP and acetylcholine (in this order) were elicited during the infusion of phenylephrine. Then, this group was subdivided into five subgroups (n=4 each) so that the infusion of phenylephrine was stopped in the first two subgroups (waiting about 60 min for the recovery of baseline external carotid blood flow), whereas it remained continuously infusing throughout the experiment in the remaining three subgroups. Subsequently, by the use of another motor-driven syringe inserted into the femoral vein and infusing at a rate of 0.5 ml min−1 during 10 min (following the procedures described for the first group): (i) the first two subgroups (60 min after stopping the phenylephrine infusion) received, consecutively, cumulative 10 min i.v. infusions of, respectively, sumatriptan (1–300 μg kg−1) and donitriptan (0.1–30 μg kg−1); and (ii) the remaining three subgroups (during phenylephrine infusion) received, consecutively, cumulative 10-min i.v. infusions of, respectively, PNU-142633 (1–300 μg kg−1), PNU-109291 (0.3–100 μg kg−1) and equivalent volumes of physiological saline (0.5 ml min−1 during 10 min; given 6 times). Then, the responses to the above doses of capsaicin, α-CGRP and acetylcholine were reanalysed. It is important to note that, with these procedures, the carotid vasoconstriction was similar in all subgroups before the 1 min intracarotid infusions of capsaicin, α-CGRP and acetylcholine. [1]
Finally, the fourth group (n=11) received an intracarotid continuous infusion of phenylephrine (1.5 μg min−1) and, 20 min later, the responses to the above doses of capsaicin were elicited as described above during the infusion of phenylephrine. At this point, this group was subdivided into three subgroups that received i.v. bolus injections of, respectively, SB224289 (300 μg kg−1; n=4), BRL15572 (300 μg kg−1; n=4) and an equivalent volume of physiological saline (0.15 ml kg−1; n=3). After 10 min, each subgroup received, consecutively, cumulative 10-min i.v. infusions of donitriptan (0.1–30 μg kg−1) as described previously. It is important to note that after the administration of SB224289 the donitriptan-induced vasoconstriction was completely blocked; therefore, in order to maintain the carotid circulation under a vasoconstriction state similar to that observed previously with the administration of this antagonist, the infusion of phenylephrine was maintained at a constant rate (1.5 μg min−1) throughout the experiments in this subgroup. In contrast, as BRL15572 or physiological saline did not modify the donitriptan-induced carotid vasoconstriction, the infusion of phenylephrine was interrupted just before the administration of these compounds (results obtained from preliminary experiments; not shown). Ten minutes after the last i.v. dose of donitriptan (30 μg kg−1) had been given, the responses to the above 1-min intracarotid infusions of capsaicin were elicited again.

[1]. Donitriptan, but not sumatriptan, inhibits capsaicin-induced canine external carotid vasodilatation via 5-HT1B rather than 5-HT1D receptors. Br J Pharmacol. 2006 Sep;149(1):82-91.

[2]. Donitriptan decreases jugular venous oxygen saturation in rats in the absence of cranial vasoconstriction: an overlooked mechanism of antimigraine action? J Pharmacol Exp Ther. 2005 Nov;315(2):849-57.

[3]. Donitriptan selectively decreases jugular venous oxygen saturation in the anesthetized pig: further insights into its mechanism of action relevant to headache relief. J Pharmacol Exp Ther . 2003 May;305(2):749-54.

Background and purpose: It has been suggested that during a migraine attack capsaicin-sensitive trigeminal sensory nerves release calcitonin gene-related peptide (CGRP), resulting in cranial vasodilatation and central nociception; hence, trigeminal inhibition may prevent this vasodilatation and abort migraine headache. This study investigated the effects of the agonists sumatriptan (5-HT(1B/1D) water-soluble), donitriptan (5-HT(1B/1D) lipid-soluble), PNU-142633 (5-HT(1D) water-soluble) and PNU-109291 (5-HT(1D) lipid-soluble) on vasodilator responses to capsaicin, alpha-CGRP and acetylcholine in dog external carotid artery. Experimental approach: 59 vagosympathectomized dogs were anaesthetized with sodium pentobarbitone. Blood pressure and heart rate were recorded with a pressure transducer, connected to a cannula inserted into a femoral artery. A precalibrated flow probe was placed around the common carotid artery, with ligation of the internal carotid and occipital branches, and connected to an ultrasonic flowmeter. The thyroid artery was cannulated for infusion of agonists. [1]

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In conclusion, the above results, taken together, suggest that the inhibition produced by donitriptan on capsaicin-induced vasodilatation of the external carotid artery is mainly mediated by 5-HT1B receptors, probably by a central mechanism.[1]

C23H25N5O2

403.4769

403.201

C, 68.47; H, 6.25; N, 17.36; O, 7.93

170912-52-4

Donitriptan hydrochloride;170911-68-9; 170912-52-4; 200615-15-2 (mesylate)

197706

White to off-white solid powder

1.32g/cm3

727.1ºC at 760mmHg

393.6ºC

5.34E-21mmHg at 25°C

1.688

2.971

2

5

6

30

618

0

SOHCKWZVTCTQBG-UHFFFAOYSA-N

InChI=1S/C23H25N5O2/c24-8-7-18-15-26-22-6-5-20(13-21(18)22)30-16-23(29)28-11-9-27(10-12-28)19-3-1-17(14-25)2-4-19/h1-6,13,15,26H,7-12,16,24H2

4-[4-[2-[[3-(2-aminoethyl)-1H-indol-5-yl]oxy]acetyl]piperazin-1-yl]benzonitrile

Donitriptan; 170912-52-4; Donitriptan [INN]; UNII-70968BVH2J; 4-[4-[2-[[3-(2-aminoethyl)-1H-indol-5-yl]oxy]acetyl]piperazin-1-yl]benzonitrile; 70968BVH2J; DONITRIPTAN [WHO-DD]; DTXSID20168974;

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)

DMSO : ~250 mg/mL (~619.61 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (5.16 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 20.8 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: ≥ 2.08 mg/mL (5.16 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 20.8 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: ≥ 2.08 mg/mL (5.16 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 20.8 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.)