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| Names | |
|---|---|
| IUPAC name 2-(Methylamino)-1-phenylethanol | |
| Other names N-Methylphenylethanolamine; 1-Hydroxy-1-phenyl-2-methylaminoethane; α-(Methylaminomethyl)benzyl alcohol; 2-Methylamino-1-phenylethanol | |
| Identifiers | |
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3D model (JSmol) | |
| ChEBI | |
| ChEMBL | |
| ChemSpider | |
| EC Number |
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| KEGG | |
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| UNII | |
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| Properties | |
| C9H13NO | |
| Molar mass | 151.209 g·mol−1 |
| Appearance | Colorless solid |
| Melting point | 43 to 45 °C (109 to 113 °F; 316 to 318 K) (R- or S- enantiomer); 75–76 °C (racemate) |
| Hazards | |
| GHS labelling: | |
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| Warning | |
| H302,H332 | |
| P261,P264,P270,P271,P301+P312,P304+P312,P304+P340,P312,P330,P501 | |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Halostachine (also known asN-methylphenylethanolamine) is anatural product, analkaloid first isolated from the Asian shrubHalostachys caspica (synonymHalostachys belangeriana), and structurally a β-hydroxy-phenethylamine (aphenylethanolamine) related to its better-known "parent"biogenic amine,phenylethanolamine, to theadrenergic drugsynephrine, and to the alkaloidephedrine. The pharmacological properties of halostachine have some similarity to those of these structurally-related compounds, andHalostachys caspica extracts have been included as a constituent of certain OTC dietary supplements,[1] but halostachine has never been developed as a prescription drug. Although it is found in nature as a singlestereoisomer, halostachine is more commonly available as a synthetic product in the form of itsracemate (see below). In appearance it is a colorless solid.
Naturally-occurring halostachine was first discovered by Syrneva in thehalophytic plantHalostachys caspica (now classed asHalostachys belangeriana[2]) (family Amaranthaceae).[3] The erroneous structure originally proposed for this compound was subsequently corrected by Menshikov and Rubinstein.[4]
Halostachine has also been isolated from perennial ryegrass,Lolium perenne and from tall fescue,Festuca arundinacea.[5][6]
The presence ofN-methylphenylethanolamine in rat brain wasimplied by the experiments described by Saavedra and Axelrod.[7]
Several syntheses of racemicN-methylphenylethanolamine have been published over the years. A synthesis using "classical" methodology was reported by Durden and co-workers, starting fromacetophenone. The methyl group of acetophenone was brominated withbromine to giveα-bromoacetophenone, which was then reacted withN-methylbenzylamine to give an amino-ketone. The amino-ketone was reduced withlithium aluminium hydride to the corresponding amino-alcohol, and theN-benzyl group finally removed bycatalytic hydrogenation using apalladium on charcoal catalyst.[8]
Another synthesis, due to Nordlander and co-workers, began with theFriedel-Crafts acylation of benzene byN-(trifluoroacetyl)glycyl chloride in the presence ofaluminum chloride. The resultingN-(trifluoroacetyl)-α-aminoacetophenone was thenN-methylated withmethyl iodide andpotassium carbonate, and the product finally converted to racemicN-methylphenylethanolamine by means ofsodium borohydride inethanol.[9]
An efficient,stereospecific synthesis of halostachine was reported by Zandbergen and co-workers: (R)-(+)-α-hydroxybenzeneacetonitrile was firstO-protected using 2-methoxypropene. The product was then treated withDIBAL, and the unisolatedimine then treated sequentially withammonium bromide andmethylamine to effect "transimination". The resultingN-methylimine was converted to (R)-(−)-α-[(methylamino)methyl]benzenemethanol (i.e. (R)-(−)-halostachine) withsodium borohydride.[10]
Chemically,N-methylphenyethanolamine is anaromatic compound, anamine, and analcohol. The amino-group makes this compound aweak base, capable of reacting with acids to form salts.
One common salt ofN-methylphenylethanolamine is the (racemic) hydrochloride, C9H13NO.HCl, m.p. 103-104 °C.[8]
ThepKa ofN-methylphenylethanolamine hydrochloride, at 25 °C and at a concentration of 10 mM, is 9.29.[11]
The presence of the hydroxy-group on thebenzylic C of theN-methylphenylethanolamine molecule creates achiral center, so the compound exists in the form of twoenantiomers, d- and l-N-methylphenylethanolamine, or as theracemic mixture, d,l-N-methylphenylethanolamine. Thedextrorotatory isomer corresponds to theS-configuration, and thelevorotatory isomer to theR-configuration.[12][13]
TheN-methylphenylethanolamine isolated fromHalostachys caspica, and given the alkaloid name "halostachine", was found to be the levorotatory enantiomer.
Halostachine has a melting point of 43-45 °C and [α]D = - 47.03°; the hydrochloride salt of this enantiomer has m.p. 113-114 °C, and [α]D = - 52.21°. Theresolution of racemicN-methylphenylethanolamine, by means of itstartrate salts, yielded enantiomers withspecific rotations of [α]D = - 52.46° and + 52.78°.[4][14]
The first pharmacological investigation of synthetic, racemicN-methylphenylethanolamine (referred to as "methylphenylethanolamine" by these authors) was carried out by Barger and Dale, who found it to be apressor, with a potency similar to that ofphenylethanolamine andβ-phenylethylamine in a cat preparation.[15] Subsequently, this compound (still in the form of its racemate) was studied more thoroughly by Chen and co-workers, who confirmed its pressor activity, but observed that it was about one-half as potent as phenylethanolamine after i.v. administration in a cat preparation: a total dose of 5 x 10−6 M (or ~ 1 mg of the HCl salt) caused a maximum rise in blood pressure of 26 mm Hg. Additional experiments by these investigators showed that racemicN-methylphenylethanolamine also causedmydriasis in the rabbit eye (instillation of a drop of 0.05 M/L solution producing about 5 x as much dilation as the same dose of phenylethanolamine), inhibition of isolated rabbit intestine strips, and contraction of isolated guinea pig uterus. The drug was also astringent on nasal mucosa.[16]
In man, an oral dose of 50 mg produced no effects on blood pressure, but this is only according to a single study from 1929.[16]
Later studies by Lands and Grant on the effects of racemicN-methylphenylethanolamine (identified by the Sterling-Winthrop company codes "WIN 5529" or "WIN 5529-2") on blood pressure in intact dogs showed similar results to those obtained by Chen et al.: 0.41 mg/kg of the drug, given i.v., caused a rise in blood pressure of 38 mm Hg lasting 3–10 minutes. This effect was described as being ~ 1/200 x that produced by the same dose of epinephrine (or ~ 1/250 x when compared on amolar basis).[17][18]
In sheep, halostachine produced only a slight mydriasis at a dose of 30 mg/kg, i.v., and "excitation" at 100 mg/kg; in guinea pigs, doses of 30 mg/kg, i.p., produced restlessness lasting about 1/2 hour, but 100 mg/kg, i.p., caused excitement, mydriasis, salivation, piloerection, muscular tremors, and increased heart and respiratory rates, with a return to normal after 1/2–2 hours.[5]
Intravenous administration of the drug to dogs, in doses of ~ 6 – 18 mg/kg, was found to produce significant mydriasis (a 100% increase in pupil diameter resulting from a dose of 17.5 mg/kg), the effect being somewhat greater (~ 1.3 x) than that produced by the same doses of phenylethanolamine.N-Methylphenylethanolamine also caused a decrease in heart rate which was inversely related to the dose (i.e. progressively larger doses caused lessbradycardia), and which was quantitatively less than that produced by the same doses of phenylethanolamine. The drug produced a fall in body temperature which was also inversely correlated with the dose, and which was smaller than that produced by the same doses of phenylethanolamine. Additional symptoms that were observed included profuse salivation andpiloerection, although, in contrast to phenylethanolamine,N-methylphenylethanolamine did not produce any stereotyped or rapid eye movements. These results led the authors to suggest thatN-methylphenylethanolamine was acting on both α and βadrenergic receptors.[19]
Using a β2adrenergic receptor preparation derived fromtransfectedHEK 293 cells, Liappakis and co-workers[20] found that inwild-type receptors, racemicN-methylphenylethanolamine (referred to by these authors as "halostachine") had ~ 1/120 x the affinity of epinephrine in competition experiments with3[H]-CGP-12177, and was therefore about 3 x more potent thanphenylethanolamine itself.[21] Measurements ofcAMP accumulation in intact transfected HEK 293 cells, after treatment withEEDQ to inactivate 98-99% of the receptors, indicated that "halostachine" was ~ 19% as effective as epinephrine in maximally-stimulating the cAMP accumulation in the wild-type receptors. "Halostachine" was thus interpreted as havingpartial agonist properties at β2 receptors.[20]
The pharmacokinetics ofN-methylphenylethanolamine, after i.v. administration to dogs, were studied by Shannon and co-workers, who found that the drug followed the "two-compartment model", with T1/2(α) ≃ 9.7 minutes and T1/2(β) ≃ 56.4 minutes; the "plasma half-life" ofN-methylphenylethanolamine was therefore about 1 hour.[19]
In animal tissue,N-methylphenylethanolamine is formed by the action of theenzymephenylethanolamine N-methyl transferase (PNMT), first isolated from monkeyadrenal glands byJulius Axelrod, on phenylethanolamine.[7][22]
The actions ofmonoamine oxidasesMAO-A andMAO-B from rat brainmitochondria onN-methylphenylethanolamine were characterized by Osamu and co-workers, who found that at a concentration of 10 μM, this compound (stereochemical identity unspecified) was a specific substrate for MAO-B, but at 100 μM and 1000 μM it became a substrate for both MAO-A and MAO-B. The kinetic constants reported by these researchers were: Km = 27.7 μM; Vmax = 3.67 nM/mg protein/30 mins (high affinity), and Km = 143 μM; Vmax = 7.87 nM/mg protein/30 mins (low affinity).[23]
The LD50 ofN-methylphenylethanolamine in mouse is reported as 44 mg/kg, i.v., and ~ 140 mg/kg, i.p. (racemic; HCl salt).;[18] in an earlier paper from the same year, Lands notes an approximate LD50 of 490 mg/kg (mouse, i.p.) for what is ostensibly the same drug, but coded as "WIN 5529", rather than "WIN 5529-2".[17]
The minimum lethal dose of the racemate in rabbits, i.v., is given as 100 mg/kg.[16]
Studies carried out to determine whether halostachine might be responsible for causing "ryegrass staggers" in Australia involved the administration of doses up to 100 mg/kg, i.v., in sheep, and 100 mg/kg, i.p., in guinea pigs, without any indication of lethality. Although apparently adrenergic effects were evident in the guinea pigs (see "Pharmacology", above), the investigators concluded that halostachine was unlikely to be the cause of the "staggers" syndrome.[5]
