2-Methoxymethyl-salvinorin B is a potent kappa opioid receptor agonist with longer lasting action in vivo than salvinorin A (2008)

[Jatelka]

A new entry has been added to Drugs Archive

Description:
Journal of Pharmacology and Experimental Therapeutics 2008 Mar;324(3):1073-83

Wang Y, Chen Y, Xu W, Lee DY, Ma Z, Rawls SM, Cowan A, Liu-Chen LY.

Salvinorin (Sal) A is a naturally occurring, selective kappa opioid receptor (KOPR) agonist with a short duration of action in vivo. Pharmacological properties of a C(2) derivative, 2-methoxymethyl (MOM)-Sal B, were characterized. MOM-Sal B bound to KOPR with high selectivity and displayed approximately 3-fold higher affinity than U50,488H [(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate] and Sal A. It acted as a full agonist at KOPR in guanosine 5'-O-(3-[(35)S]thio)triphosphate binding and was approximately 5- and approximately 7-fold more potent than U50,488H and Sal A, respectively. In Chinese hamster ovary cells stably expressing KOPR, all three kappa agonists internalized or down-regulated KOPR to similar extents, with MOM-Sal B being the most potent. In mice, MOM-Sal B (0.05-1 mg/kg s.c.) caused immediate and dose-dependent immobility lasting approximately 3 h, which was blocked by norbinaltorphimine. In contrast, ambulation in a Y-maze was increased when rats received MOM-Sal B (1-5 mg/kg s.c.). In addition, MOM-Sal B (0.5-5 mg/kg i.p.) produced antinociception (hot-plate test) and hypothermia in a dose-dependent manner in rats. MOM-Sal B was more potent than U50,488H in both tests and more efficacious than U50,488H in the hot-plate test. These latter two in vivo effects were blocked by norbinaltorphimine, indicating KOPR-mediated actions. Sal A at 10 mg/kg elicited neither antinociception nor hypothermia 30 min after administration to rats. In summary, MOM-Sal B is a potent and efficacious KOPR agonist with longer lasting in vivo effects than Sal A.

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[DividedReality]

Very interesting, I am surprised that they think it is 5 to 7 times more powerfull. People who are already sensitive to the A form would have to be very carefull with B. But this may be the answer for hardheads :0

[Salvinorin A]

wow, SWIM actually just read this a few days ago (thanks for putting it in the archive).

This is really incredible. Can any swimmer even imagine a more powerful salvia trip.....that lasts 3 hours???? The sal trip may not even be just a confusing mindf*ck anymore....but actually some time for introspection...who knows?

However, two things come to mind.

1. Could any swimmer get a hold of this chemical? The synthesis seems a little beyond kitchen chemistry from what it looks like. What would ingestion be like? Would IV be the only effective way?

2. The dosage. The amount theyr'e giving these rats (the Sal-A as well) would knock any swimmer into a level 6 trip...........and the tripper would have no memory of what happened (more like an anaesthetic for surgery). But even, Sal-A is already very potent....if MOM-Sal-B is ever put in a form for human use....how low would it's threshold effect dose be? would it rival LSD?

Crazy, crazy....swim wishes he had the knowledge to further research things like this.

Sal-A

EDIT:

Synthesis: from http://www.freepatentsonline.com/y2007/0213394.html

[top]Synthesis of 2-methoxymethyl-salvinorin B (Compound 8)

10 mg of compound 1 was dissolved in 5 mL of anhydrous CH 2 Cl 2 to which was added a catalytic amount of DMAP (1 mg), N,N-Diisopropylethylamine (2 eq) and MOM-Cl (2 eq) at room temperature and the reaction was stirred for 48 hours. After completion of the reaction, water was added (10 mL) to the reaction mixture followed by extraction with EtOAc (2×10 mL). The organic layer was dried (Na 2 SO 4 ) and concentrated to afford a crude mixture. The crude mixture was further purified by column chromatography (1:2, EtOAc:Hexane) to give the pure compound 8. 1 H-NMR: (300 MHz, CDCl 3 ) δ 7.41 (d, 2H), 6.39 (d, J=0.6 Hz, 1H), 5.55 (dd, J=5.1, 11.7 Hz, 1H), 4.72 (q, 2H), 4.14 (dd, J=7.2, 12 Hz, 1H), 3.72 (s, 3H), 3.39 (s, 3H), 2.69 (dd, J=3.6, 13.5 Hz, 1H), 2.54 (dd, J=5.1, 13.2 Hz, 1H), 2.38-2.32 (m, 1H), 2.27-2.03 (m, 4H), 1.81-1.53 (m, 5H), 1.47 (s, 3H), 1.26 (s, 3H), 1.21 (s. 3H). 13 C-NMR: (70.5 MHz, CDCl 3 ) δ 205.8, 171.8, 171.2, 143.7, 139.4, 125.3, 108.3, 95.7, 77.8, 71.9, 64.3, 55.8, 53.9, 51.9, 51.5, 43.6, 41.9, 38.2, 35.5, 32.6, 18.1, 16.4, 15.2.

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Compound 1 is Salvinorin B:

[top]Synthesis of Salvinorin B (Compound 1)

To a cold (0° C.) solution of salvinorin A (153.0 mg, 0.35 mmol) in MeOH (3 mL) and CH 2 Cl 2 (3 mL) was added K 2 CO 3 (98 mg, 0.71 mmol) and the mixture was stirred at 0° C. (20 minutes). Water (5 mL) and CH 2 Cl 2 (5 mL) were added to the reaction mixture. The organic layer was concentrated in vacuo and then purified by column chromatography (SiO 2 ; 4:1, CH 2 Cl 2 :EtOAc) to obtain 66 mg (48%) of pure 1 as a white solid: R f 0.23 (1:1, EtOAc:hexanes); 1 H NMR (CDCl 3 ) δ 1.10 (s, 3H), 1.49 (s, 3H), 1.51-1.69 (m, 3H), 1.77-1.82 (m, 1H), 2.02-2.10 (m, 2H), 2.14-2.20 (m, 1H), 2.17 (s, 1H), 2.45-2.50 (m, 1H), 2.55 (dd, 1H), 2.71 (dd, 1H), 3.60 (d, 1H), 3.72 (s, 3H), 4.05-4.12 (m, 1H), 5.57 (dd, 1H), 6.38 (s, 1H), 7.40-7.42 (m, 2H); 13 C NMR (CDCl 3 ) 15.2, 16.5, 18.1, 34.5, 35.4, 38.1, 42.6, 43.5, 51.3, 51.9, 53.1, 63.8, 71.9, 74.3, 108.3, 125.3, 139.3, 143.8, 171.1, 171.8, 208.9 ppm.

[Panthers007]

If this stuff is triggering opiate receptors, as an agonist, I would be concerned about other possible effects. Such as to respiration. Bringing to mind the use of fentanyl derivatives as chemical incapacitating agents (Moscow theater hostage situation). Extreme caution would be the proper approach.

[Salvinorin A]

^^^ This is very true. The thing is, Salvinorin A seems to do a good job of avoiding respiratory depression, if swim remembers correctly...it's because it very selectively only goes to the Kappa receptor, and has little affinity to the other opiate receptors (usually the ones that cause respiratory problems at high doses).

Salvinorin A for example, is very very potent....especially to humans.....considering the amount they give rats for tests....and that the rats wake up just fine....it seems like a good sign. The rats in the MOM-Sal-B seemed to come out fine as well. But who knows, maybe MOM-Sal-B affects other things in humans. SWIM would gladly volunteer use...and is hoping that some sort of study on humans will eventually happen.

Sal-A

[Alfa]

You might find this one interesting as well:
Salvinorin A analogues

[Ididnotinhale]

Swim is a little confused, it is a Kappa opiod receptor agonist? Swim knows that opioids generally work on the Mu receptors, but secondarily on the Kappa receptors, so it seems like this drug would also give an opiate high? If someone could explain this it would be much appreciated. Thanks

[Salvinorin A]

Salvinorin A selectively acts on the Kappa opioid receptors....unlike most other opiates......which do as swiy described, Salvinorin A specifically binds to the kappa one....and barely touches ones like the mu.

This is why there are such intense hallucinations on Sal-A, a lack of euphoria.....and why it's hard to get addicted to. But don't quote swim on this one...but swim thinks that it mildly binds to other receptors like the mu...which is why people who lack opiate tolerance (at least from what swim has seen.........get a mild euphoria on Salvia..........swim never gets it....usually dysphoria for swim and a lot of people...the laughing doesn't really count).

Sal-A