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| Names | |
|---|---|
| Preferred IUPAC name 4-[2-(Dimethylamino)ethyl]benzene-1,2-diol | |
| Identifiers | |
3D model (JSmol) | |
| ChemSpider | |
| UNII | |
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| Properties | |
| C10H15NO2 | |
| Molar mass | 181.235 g·mol−1 |
| Appearance | colorless |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
N,N-Dimethyldopamine (DMDA) is anorganic compound belonging to thephenethylamine family. It is related structurally to thealkaloidepinine (N-methyldopamine) and to the majorneurotransmitterdopamine (of which it is theN,N-dimethylated analog). Because of its structural relationship to dopamine, DMDA has been the subject of a number of pharmacological investigations.DMDA has been detected inAcacia rigidula.
DMDA has been reported from the plantAcacia rigidula Benth. (Fabaceae), in which it has been detected at levels of ~ 11-45 ppm.[1]
SinceN,N-dimethyldopamine is chemically an amine, it is basic (aweak base, technically), but it is also acatechol (a 1,2-dihydroxybenzene), which gives itweakly acidic properties, so that the compound isamphoteric.
Several different methods have been reported for the preparation of DMDA. An early synthesis by Buck and co-workers began with3,4-dimethoxybenzaldehyde (veratraldehyde), which was condensed withhippuric acid to give theazlactone; this was hydrolyzed withNaOH to the correspondingpyruvic acid, which was then converted to itsoxime; treatment of the oxime withacetic anhydride gave 3,4-dimethoxyphenylacetonitrile, which was catalytically reduced (H2/Pd) in the presence of excessdimethylamine to N,N-dimethyl-3,4-dimethoxyphenethylamine; finally, the methoxy-groups were cleaved withHCl to give DMDA as its hydrochloride salt.[2]
A more recent method starts with 3,4-dimethoxyphenylacetic acid, which is converted to itsacid chloride withthionyl chloride; this is reacted withdimethylamine to give the dimethylamide, which is then reduced usingdiborane to N,N-dimethyl 3,4-dimethoxyphenethylamine; the methoxy- groups are finally cleaved withhydriodic acid to give DMDA.[3]
The shortest method is that of Borgman et al., who converted 3,4-dimethoxyphenethylamine intoN,N-dimethyl 3,4-dimethoxyphenethylamine by catalytic reduction (H2/Pd) in the presence offormaldehyde; the methoxy-groups were then cleaved withhydrobromic acid.[4]
One of the earliest pharmacological studies of DMDA was that of Daly and his co-workers, who studied the ability of a large number of substituted phenethylamines to releasenorepinephrine (NE) from the mouse heart. In this assay, a subcutaneous dose of 10 mg/kg of DMDA hydrochloride (referred to as "3,4-dihydroxy-N,N-dimethylphenethylamine HCl") failed to produce a significant change in the NE content of the heart. In comparison, a dose of 5 mg/kg, s.c., of N-methyldopamine ("3,4-dihydroxy-N-methylphenethylamine HCl") caused a 45% reduction in the NE content, while dopamine HCl itself caused a 50% decrease at a dose of 5 mg/kg, s.c.[5]
Another early pharmacological investigation of DMDA was carried out by Goldberg and co-workers, who examined the effects of a range ofphenethylamine analogs in an assay based on thevasodilation produced by injection of the test drug into therenal artery of the dog. In this assay, a drug was classed as "dopamine-like" if the vasoldilation it produced was not prevented byβ-blocking drugs, and did not occur if the drug was injected into thefemoral artery. Although DMDA, at a dose of 0.5 mg, caused a markedbradycardia, a dose of ~ 0.75 mg did not increase renal blood flow (i.e. cause vasodilation) after administration ofatropine to abolish the bradycardia.[6]
In cats pretreated withatropine andhexamethonium, DMDA is a strongvasopressor: aparenteral dose of 10 μg/kg produced a rise in blood pressure more than twice that produced by the same dose of dopamine. In an assay based on the increase in heart rate (positive chronotropic response) produced by electrical stimulation of the post-ganglionic fibers of catcardioaccelerator nerve, an i.v. dose of ~ 15 μg/kg DMDA caused a 50% reduction of the response, compared to an approximately 10% decrease produced by the same dose of dopamine. From these and other related observations, the researchers concluded that DMDA was a potent inhibitor of theadrenergic system via stimulation of inhibitory putative (at that time) dopamine receptors on adrenergic nerve terminals.[7]
In the dog, an i.v. dose of 16 μg/kg caused an ~ 80% decrease in heart rate in the same cardioaccelerator nerve assay, compared to an ~ 8% decrease produced by dopamine. DMDA caused vasoconstriction in several isolated vascular preparations from the rabbit. The pressor activity of DMDA was partially inhibited by the α-antagonistphentolamine. From these and other observations, the investigators concluded that there were significant species-related differences between the responses to DMDA of dogs and cats, with adrenergic effects being predominant in dogs.[8]
Ginos et al. tested DMDA for effects inunilaterally-caudectomized mice (dose ≤ 120 mg/kg, i.p.), nigral-lesioned rats (dose = 10 mg/kg, i.p.), and onadenylate cyclase activity in homogenized mousecaudate nuclei (concentration = 10μM/L). DMDA showed no effects in any of these assay systems. By comparison,N-methyldopamine also had no effect in caudectomized mice at ≤ 150 mg/kg, and only a weak effect in nigral-lesioned rats at 25 mg/kg, although it was as effective as dopamine in stimulatingcAMP in the adenylate cyclase assay.[3]
Borgman and co-workers reported in 1973 that at 100 mg/kg, given i.p. to mice, DMDA failed to antagonize the tremor and reduction in locomotor activity produced by pre-administration ofoxotremorine. In another assay, 6 mg/kg of DMDA (i.p. in mice) only slightly antagonized the reduced locomotor activity resulting from pre-treatment withreserpine. A dose of 1 mg/kg, iv., of DMDA did not produce anyhypothermia in mice.[4]
It has been stated that dopamine is behaviorally inactive due to its rapid peripheral metabolism and inability to cross theblood–brain barrier.[9] When dopamine orN-methyldopamine were injected directly into thenucleus accumbens of mice, however, doses of 12.5-50 μg produced marked hyperactivity, with the latter being somewhat more potent. In contrast, DMDA did not produce any hyperactivity in doses up to 100 μg.[10]
In a 1981 paper, Costall and co-workers reported that DMDA, in doses of 0.5–8 mg/kg given i.p. to mice, produced a dose-dependent reduction in spontaneous motor activity (occurring within a 20 minute period after drug administration). They also observedpiloerection at 2 mg/kg, and prostration accompanying the 8 mg/kg or higher doses. The effects of DMDA were not altered by the administration ofspiroperidol.[11]
Receptor binding studies, in competition with [3H]-spiperone, using receptors from piganterior pituitary, have revealed the following affinities for D2 receptors exhibited by DMDA: Kahigh = 20 nM; Kalow = 10200 nM. In comparison, the corresponding affinities forN-methyldopamine are: 10.4 nM (high) and 3430 nM (low), while for dopamine they are 7.5 nM (high) and 4300 nM (low affinity state).[12]
Similar receptor binding results were obtained when DMDA and DA were assayed using a receptor preparation from ratstriatum: competition against [3H]-spiperone gave affinity constants of ~ 25 nM (high affinity state) and ~ 724 nM (low) for DMDA, compared to ~ 10 nM (high) and ~ 354 nM (low) for dopamine. Both drugs were also tested for their ability to inhibit the [3H]-ACh release from mouse striatal slices evoked by K+. In this assay, the ED50 for DMDA was ~ 0.06 μM, and for dopamine it was ~ 1.9 μM.[13]
The LD50 forN,N-dimethyldopamine·HCl is reported as 240 mg/kg (mouse, i.p.).;[3] under the same experimental conditions, the LD50 for N-methyldopamine.HBr (epinine hydrobromide) is 212 mg/kg (mouse, i.p.), and the LD50 for dopamine·HCl is 1978 mg/kg (mouse, i.p.).[3]
