(S)-Nornicotine hydrochloride
(S)-Nornicotine hydrochloride is a nicotine metabolite that crosses the blood-brain barrier. (S)-Nornicotine hydrochloride weakly inhibits human CYP2A6 with a Ki >300 μM. (S)-Nornicotine hydrochloride promotes dopamine release in rat striatal and nucleus accumbens slices and increases endogenous DOPAC overflow through a calcium-dependent nAChR pathway that is sensitive to Mecamylamine (HY-B1395A). (S)-Nornicotine hydrochloride reduces behavioral responses maintained by nicotine or sucrose, exerts analgesic effects in persistent inflammatory pain and neuropathic pain models, and enhances the analgesic effect of morphine. (S)-Nornicotine hydrochloride is useful for research on tobacco dependence and pain.
For research use only. We do not sell to patients.
- CAS No.: 101832-65-9
- Formula: C9H13ClN2
- Molecular Weight:184.67
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Please store the product under the recommended conditions in the Certificate of Analysis.
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Biological Activity
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Biological Activity
Description
(S)-Nornicotine hydrochloride is a nicotine metabolite that crosses the blood-brain barrier. (S)-Nornicotine hydrochloride weakly inhibits human CYP2A6 with a Ki >300 μM. (S)-Nornicotine hydrochloride promotes dopamine release in rat striatal and nucleus accumbens slices and increases endogenous DOPAC overflow through a calcium-dependent nAChR pathway that is sensitive to Mecamylamine (HY-B1395A). (S)-Nornicotine hydrochloride reduces behavioral responses maintained by nicotine or sucrose, exerts analgesic effects in persistent inflammatory pain and neuropathic pain models, and enhances the analgesic effect of morphine. (S)-Nornicotine hydrochloride is useful for research on tobacco dependence and pain[1][2][3][4].
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CYP2A6 ≥300 μM (Ki) |
Human Endogenous Metabolite |
In Vitro
(S)-Nornicotine (0.1-100 μM) hydrochloride induces a concentration-dependent and sustained overflow of endogenous DOPAC in a rat striatal brain slice perfusion model, with no significant desensitization[1].
(S)-Nornicotine (0.01-1.0 μM) hydrochloride does not modulate electrically stimulated overflow of endogenous DOPAC from superfused rat striatal slices[1].
(S)-Nornicotine (0.1-100 μM) hydrochloride induces a concentration-dependent tritium overflow in the perfusate of rat striatal brain slices preloaded with [3H]DA, which is consistent with a direct stimulatory effect on dopamine release[1].
(S)-Nornicotine (10-100 μM; 15 min) hydrochloride induces a calcium-dependent increase in endogenous DOPAC efflux in superfused rat striatal slices[1].
(S)-Nornicotine (0.02-400 μM; 10 min) hydrochloride is a weak inhibitor of CYP2A6-mediated coumarin 7-hydroxylation expressed in human lymphoblastoid cells, with a Ki value ≥300 μM[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
In Vivo
(S)-Nornicotine (1-10 mg/kg; subcutaneous injection) hydrochloride dose-dependently reduces intravenous S (-)-nicotine self-administration behavior in rats[2].
(S)-Nornicotine (1-10 mg/kg; s.c.) hydrochloride dose-dependently decreases sucrose-maintained responding in rats, with potency comparable to that of R (+)-nornicotine[2].
(S)-Nornicotine (5.6-10 mg/kg; subcutaneous injection) hydrochloride dose-dependently reduces the duration of action of S (-)-nicotine self-administration[2].
(S)-Nornicotine (3-5.6 mg/kg; subcutaneous injection; once daily; for 10 consecutive days) hydrochloride persistently reduces S (-)-nicotine self-administration behavior in rats over 10 days without producing tolerance[2].
(S)-Nornicotine (5.6 mg/kg; subcutaneous injection; single dose) hydrochloride reaches a mean brain concentration of 214.6 ng/mL in rats, and its brain exposure is similar to that of R (+)-nornicotine[2].
(S)-Nornicotine (5.6 mg/kg; subcutaneous injection; once daily; for 9 consecutive days) hydrochloride causes sustained increases in blood pressure and heart rate in rats without producing tolerance[2].
(S)-Nornicotine (0.5-20 mg/kg; i.p.; single dose) hydrochloride produces dose-dependent inhibition of formalin-induced flinching behavior in both phases of the rat formalin test, with similar potency in phase 1 and phase 2 (ED50 approximately 1.5-1.8 mg/kg i.p.)[3].
(S)-Nornicotine (10-40 mg/kg; i.p.) hydrochloride produces moderate dose-dependent antinociception in the acute thermal paw test in rats, with an i.p. ED50 of 29.3 mg/kg[3].
(S)-Nornicotine (2.5-20 mg/kg; i.p.) hydrochloride produces motor side effects at doses above those required for analgesia, with tactile allodynia showing the greatest dose separation[3].
(S)-Nornicotine (2.5 mg/kg; 10-100 μg; i.p.; intrathecal injection) hydrochloride does not exhibit significant antinociceptive activity in the rat tail-flick test[3].
(S)-Nornicotine (2.5 mg/kg; 10-100 μg; i.p.; intrathecal injection) hydrochloride at sub-analgesic doses enhances the antinociceptive effect of morphine in the rat tail-flick test, and when administered intrathecally, the combination with morphine achieves approximately 100% of the maximum possible effect[3].
(S)-Nornicotine (0.01-7.5 mg/kg; i.p.; p.o.) hydrochloride at subanalgesic doses enhances the antihyperalgesic effect of morphine in the rat CCI model, achieving 100% MPE at the combination dose without motor impairment as assessed by the rotarod test[3].
(S)-Nornicotine (1-10 mg/kg; s.c.) hydrochloride dose-dependently decreases sucrose-maintained responding in rats, with potency comparable to that of R (+)-nornicotine[2].
(S)-Nornicotine (5.6-10 mg/kg; subcutaneous injection) hydrochloride dose-dependently reduces the duration of action of S (-)-nicotine self-administration[2].
(S)-Nornicotine (3-5.6 mg/kg; subcutaneous injection; once daily; for 10 consecutive days) hydrochloride persistently reduces S (-)-nicotine self-administration behavior in rats over 10 days without producing tolerance[2].
(S)-Nornicotine (5.6 mg/kg; subcutaneous injection; single dose) hydrochloride reaches a mean brain concentration of 214.6 ng/mL in rats, and its brain exposure is similar to that of R (+)-nornicotine[2].
(S)-Nornicotine (5.6 mg/kg; subcutaneous injection; once daily; for 9 consecutive days) hydrochloride causes sustained increases in blood pressure and heart rate in rats without producing tolerance[2].
(S)-Nornicotine (0.5-20 mg/kg; i.p.; single dose) hydrochloride produces dose-dependent inhibition of formalin-induced flinching behavior in both phases of the rat formalin test, with similar potency in phase 1 and phase 2 (ED50 approximately 1.5-1.8 mg/kg i.p.)[3].
(S)-Nornicotine (10-40 mg/kg; i.p.) hydrochloride produces moderate dose-dependent antinociception in the acute thermal paw test in rats, with an i.p. ED50 of 29.3 mg/kg[3].
(S)-Nornicotine (2.5-20 mg/kg; i.p.) hydrochloride produces motor side effects at doses above those required for analgesia, with tactile allodynia showing the greatest dose separation[3].
(S)-Nornicotine (2.5 mg/kg; 10-100 μg; i.p.; intrathecal injection) hydrochloride does not exhibit significant antinociceptive activity in the rat tail-flick test[3].
(S)-Nornicotine (2.5 mg/kg; 10-100 μg; i.p.; intrathecal injection) hydrochloride at sub-analgesic doses enhances the antinociceptive effect of morphine in the rat tail-flick test, and when administered intrathecally, the combination with morphine achieves approximately 100% of the maximum possible effect[3].
(S)-Nornicotine (0.01-7.5 mg/kg; i.p.; p.o.) hydrochloride at subanalgesic doses enhances the antihyperalgesic effect of morphine in the rat CCI model, achieving 100% MPE at the combination dose without motor impairment as assessed by the rotarod test[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Sprague-Dawley (male; 230-300 g at start; intravenous S(-)-nicotine self-administration model under FR5 20-sec signaled timeout schedule)[2]
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Dosage:1 mg/kg, 3 mg/kg, 5.6 mg/kg, 10 mg/kg
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Administration:s.c.; acute pretreatment 15 min before self-administration sessions; Latin Square within-subjects design
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Result:Decreased S(-)-nicotine self-administration in a dose-dependent manner, with significant decreases at 5.6 mg/kg and 10 mg/kg.
Did not significantly alter inactive lever responding.
Decreased responding throughout the entire 60-min session.
Showed lower potency than R(+)-nornicotine, with responding following 5.6 and 10 mg/kg significantly higher than following the same doses of R(+)-nornicotine.
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Animal Model:Sprague-Dawley (male; 230-300 g at start; operant conditioning model with 45 mg sucrose pellet reinforcement under FR5 schedule)[2]
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Dosage:1 mg/kg, 3 mg/kg, 5.6 mg/kg, 10 mg/kg
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Administration:s.c.; acute pretreatment 15 min before sucrose responding sessions; Latin Square within-subjects design
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Result:Decreased sucrose-maintained responding in a dose-dependent manner.
Showed equipotency to R(+)-nornicotine with no enantioselectivity observed.
Affected specifically the active lever responding.
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Animal Model:Sprague-Dawley (male; 230-300 g at start; intravenous S(-)-nicotine self-administration model under FR5 20-sec signaled timeout schedule)[2]
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Dosage:5.6 mg/kg, 10 mg/kg
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Administration:s.c.; acute pretreatment at 15, 60, 120, and 240 min before self-administration sessions; within-subjects randomized order
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Result:Produced a similar magnitude of decrease in S(-)-nicotine self-administration at 5.6 mg/kg as 3.0 mg/kg R(+)-nornicotine, with effect lasting up to 60 min.
Produced a similar magnitude of decrease in S(-)-nicotine self-administration at 10 mg/kg as 5.6 mg/kg R(+)-nornicotine, with effect lasting up to 240 min.
Exhibited a time-dependent loss of effect across increasing pretreatment intervals, with similar time course between enantiomers at equally effective doses.
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Animal Model:Sprague-Dawley (male; 230-300 g at start; intravenous S(-)-nicotine self-administration model under FR5 20-sec signaled timeout schedule with repeated pretreatment)[2]
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Dosage:3 mg/kg, 5.6 mg/kg
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Administration:s.c.; once daily 15 min before self-administration sessions; 10 consecutive days
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Result:Decreased S(-)-nicotine self-administration compared to saline across all 10 sessions at both 3 mg/kg and 5.6 mg/kg.
Produced a greater decrease at 5.6 mg/kg than at 3 mg/kg on sessions 1-6.
Did not induce tolerance to the rate-decreasing effect across repeated pretreatments.
Showed a smaller decrease than 5.6 mg/kg R(+)-nornicotine on sessions 1, 3, and 6, with enantioselectivity dissipating across repeated treatments.
Resulted in continued decreased responding in the 5.6 mg/kg dose group on the first saline substitution session after termination, with no significant difference on the second saline session.
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Animal Model:Sprague-Dawley (male; 230-300 g at start; brain pharmacokinetic assessment following acute systemic administration)[2]
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Dosage:5.6 mg/kg
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Administration:s.c.; single acute injection; terminal brain sampling at 60 min post-dose
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Result:Reached a mean brain concentration of 214.6 ng/mL 60 min after s.c. administration.
Showed brain levels not significantly different from brain levels of R(+)-nornicotine at the same dose and time point.
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Animal Model:Sprague-Dawley (male; 230-300 g at start; prior history of nornicotine treatment; minimum 14 drug-free days before testing; cardiovascular function assessment via radiotelemetry following repeated administration)[2]
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Dosage:5.6 mg/kg
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Administration:s.c.; once daily; 9 consecutive days; 2-hr cardiovascular recording post-injection each day
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Result:Increased mean arterial blood pressure (MAP) and heart rate acutely on Day 1.
Did not induce tolerance to the MAP-elevating effect across 9 days of repeated treatment, with MAP remaining significantly elevated relative to saline control on Day 9.
Did not induce tolerance to the heart rate-elevating effect across 9 days of repeated treatment, with heart rate remaining significantly elevated relative to saline on Day 9.
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Animal Model:Sprague-Dawley (male; ~90 days old; ~350 g; subcutaneous injection of 50 μL 5% formalin into dorsal surface of left hind paw)[3]
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Dosage:0.5, 2.5, 5, 10, 20 mg/kg
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Administration:i.p.; 15 min prior to formalin injection; single dose
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Result:Inhibited formalin-induced flinching in both the early (0-10 min) and late (20-60 min) phases in a dose-related manner.
Had an ED50 of 1.8 mg/kg i.p. for the 1st phase.
Had an ED50 of 1.5 mg/kg i.p. for the 2nd phase.
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Animal Model:Sprague-Dawley (male; ~90 days old; ~350 g; intact; thermal plantar test using radiant heat)[3]
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Dosage:10, 20, 30, 40 mg/kg
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Administration:i.p.; randomized doses with weekly intervals between treatments
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Result:Caused a dose-dependent increase in paw withdrawal latency, with an ED50 of 29.3 mg/kg i.p.
Could not be tested at doses above 40 mg/kg i.p. due to toxicity.
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Animal Model:Sprague-Dawley (male; ~90 days old; ~350 g; intact; motor side effect assessment via rotarod, locomotor activity, ataxia, activity level)[3]
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Dosage:2.5, 5, 10, 20 mg/kg
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Administration:i.p.; randomized doses with 48 h intervals (rotarod)
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Result:Caused dose-related motor incoordination on the rotarod, with an ED50 of 13.6 mg/kg i.p.
Did not produce a statistically significant decrease in locomotor activity compared to saline.
Produced dose-related ataxia.
Produced dose-related decreases in overall activity level.
Had less pronounced ataxia and activity level decreases than the R(+)-enantiomer.
Had a therapeutic index ratio (ED50 rotarod / ED50 analgesia) of ~3 for mechanical hyperalgesia.
Had a therapeutic index ratio of ~90 for tactile allodynia.
Had a therapeutic index ratio of ~9 for formalin 2nd phase flinching.
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Animal Model:Sprague-Dawley (male; ~90 days old; ~350 g; intact; tail-flick test using thermal stimulation; some with chronic spinal subarachnoid catheterization)[3]
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Dosage:2.5 mg/kg (i.p.); 10, 30, 100 μg (i.t.)
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Administration:i.p.; i.t.
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Result:Had no antinociceptive activity on its own at 2.5 mg/kg i.p.
Did not produce significant antinociception across the 10-100 μg i.t. dose range, with %MPE values remaining near the saline level (~10% or less).
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Animal Model:Sprague-Dawley (male; ~90 days old; ~350 g; intact; tail-flick test; some with chronic spinal subarachnoid catheterization; this compound in combination with morphine)[3]
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Dosage:2.5 mg/kg (i.p., combined with 3 mg/kg morphine i.p.); 10, 30, 100 μg (i.t., combined with 0.5 μg morphine i.t.)
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Administration:i.p. (combination with morphine); i.t. (combination with morphine)
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Result:Enhanced the antinociception produced by 3 mg/kg morphine i.p. at a sub-analgesic dose of 2.5 mg/kg i.p. in the tail-flick test.
Enhanced the effectiveness of this compound at doses that had no antinociceptive activity alone when combined with 0.5 μg morphine i.t.
Achieved a maximum effect of ~100% MPE with the combination of 0.5 μg morphine i.t. and 100 μg this compound i.t.
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Animal Model:Sprague-Dawley (male; ~90 days old; ~350 g; chronic constriction nerve injury;this compound in combination with morphine)[3]
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Dosage:0.01, 0.05, 0.1, 0.5 mg/kg (i.p., combined with 3 mg/kg morphine i.p.); 0.1, 0.5, 1, 5, 7.5 mg/kg (p.o., combined with 5 mg/kg morphine p.o.)
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Administration:i.p. (combination with morphine); p.o. (combination with morphine)
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Result:Produced dose-related antihyperalgesia in the presence of low-dose morphine via both i.p. and p.o. routes at doses with no significant antihyperalgesic activity alone.
Achieved maximum efficacy of 100% MPE with 0.5 mg/kg this compound i.p. plus 3 mg/kg morphine i.p.
Achieved maximum efficacy of 100% MPE with 7.5 mg/kg this compound p.o. plus 5 mg/kg morphine p.o.
Showed no motor effect at the combination doses tested on the rotarod: 3 mg/kg this compound i.p. plus 3 mg/kg morphine i.p., and 7.5 mg/kg this compound p.o. plus 5 mg/kg morphine p.o., as rats remained on the rotarod for the full 180 s cut-off.
Chemical Information
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CAS No. 101832-65-9
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Molecular Weight 184.67
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Formula C9H13ClN2
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SMILES
[H]Cl.C1([C@H]2NCCC2)=CC=CN=C1
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Structure Classification
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Initial Source
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Shipping
Room temperature in continental US; may vary elsewhere.
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Storage
Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
Select Batch:
Purity:
99.98%
Assay:
99.98%
ee.:
99.98%
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(S)-Nornicotine hydrochloride Related Classifications
HY-W040430A Related Classifications
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