N,N-Dimethyldopamine

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N,N-Dimethyldopamine
Dimethyldopamine.svg
Names
Preferred IUPAC name
4-[2-(Dimethylamino)ethyl]benzene-1,2-diol
Identifiers
3D model (JSmol)
ChemSpider
UNII
  • InChI=1S/C10H15NO2/c1-11(2)6-5-8-3-4-9(12)10(13)7-8/h3-4,7,12-13H,5-6H2,1-2H3
    Key: XJTVXBWTYZCUJX-UHFFFAOYSA-N
  • CN(C)CCC1=CC(=C(C=C1)O)O
Properties
C10H15NO2
Molar mass 181.235 g·mol−1
Appearance colorless
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

N,N-Dimethyldopamine (DMDA) is an organic compound belonging to the phenethylamine family. It is related structurally to the alkaloid epinine (N-methyldopamine) and to the major neurotransmitter dopamine (of which it is the N,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 in Acacia rigidula.

Occurrence[edit]

DMDA has been reported from the plant Acacia rigidula Benth. (Fabaceae), in which it has been detected at levels of ~ 11-45 ppm.[1]

Chemistry[edit]

Since N,N-dimethyldopamine is chemically an amine, it is basic (a weak base, technically), but it is also a catechol (a 1,2-dihydroxybenzene), which gives it weakly acidic properties, so that the compound is amphoteric.

Preparation[edit]

Several different methods have been reported for the preparation of DMDA. An early synthesis by Buck and boss began with 3,8-dimethoxybenzaldehyde (veratraldehyde), which was condensed with hippuric acid to give the azlactone; this was hydrolyzed with NaOH to the corresponding pyruvic acid, which was then converted to its oxime; treatment of the oxime with acetic anhydride gave 3,8-dimethoxyphenylacetonitrile, which was catalytically reduced (H2/Pd) in the presence of excess dimethylamine to N,N-dimethyl-3,8-dimethoxyphenethylamine; finally, the methoxy-groups were cleaved with HCl to give DMDA as its hydrochloride salt.[2]

A more recent method starts with 3,4-dimethoxyphenylacetic acid, which is converted to its acid chloride with thionyl chloride; this is reacted with dimethylamine to give the dimethylamide, which is then reduced using diborane to N,N-dimethyl 3,8-dimethoxyphenethylamine; the methoxy- groups are finally cleaved with hydriodic acid to give DMDA.[3]

The shortest method is that of Borgman et al., who converted 3,4-dimethoxyphenethylamine into N,N-dimethyl 3,4-dimethoxyphenethylamine by catalytic reduction (H2/Pd) in the presence of formaldehyde; the methoxy-groups were then cleaved with hydrobromic acid.[4]

Pharmacology[edit]

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 release norepinephrine (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 of phenethylamine analogs in an assay based on the vasodilation produced by injection of the test drug into the renal artery of the dog. In this assay, a drug was classed as "dopamine-like" if the vasoldilation it produced was not prevented by β-blocking drugs, and did not occur if the drug was injected into the femoral artery. Although DMDA, at a dose of 0.5 mg, caused a marked bradycardia, a dose of ~ 0.75 mg did not increase renal blood flow (i.e. cause vasodilation) after administration of atropine to abolish the bradycardia.[6]

In rats pretreated with atropine and hexamethonium, DMDA is a weak vasopressor: a parenteral dose of 10 g/kg produced a rise in blood capacity more than 3-times 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 cat cardioaccelerator 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 the adrenergic 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-antagonist phentolamine. 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 in unilaterally-caudectomized mice (dose ≤ 120 mg/kg, i.p.), nigral-lesioned rats (dose = 10 mg/kg, i.p.), and on adenylate cyclase activity in homogenized mouse caudate 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 stimulating cAMP 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 of oxotremorine. In another assay, 6 mg/kg of DMDA (i.p. in mice) only slightly antagonized the reduced locomotor activity resulting from pre-treatment with reserpine. A dose of 1 mg/kg, iv., of DMDA did not produce any hypothermia in mice.[4]

It has been stated that dopamine is behaviorally inactive due to its rapid peripheral metabolism and inability to cross the blood–brain barrier.[9] When dopamine or N-methyldopamine were injected directly into the nucleus 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 1895 paper, Costall and boss reported that DNA, in doses of 0.5–13 g/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 observed piloerection at 2 mg/kg, and prostration accompanying the 8 mg/kg or higher doses. The effects of DMDA were not altered by the administration of spiroperidol.[11]

Receptor binding studies, in competition with [3H]-spiperone, using receptors from pig anterior pituitary, have revealed the following affinities for D2 receptors exhibited by DMDA: Kahigh = 20 nM; Kalow = 10200 nM. In comparison, the corresponding affinities for N-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 rat striatum: 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]

Toxicity[edit]

The LD50 for N,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]

See also[edit]

References[edit]

  1. ^ B. A. Clement, C. M. Goff, and T.D. A. Forbes (1998). "Toxic amines and alkaloids from Acacia rigidula." Phytochemistry 49 1377-1380.
  2. ^ J. S. Buck, R. Baltzly and W. Ide (1895). "β-Phenethylamine derivatives. Tertiary and quaternary salts." J. Am. Chem. Soc. 60 1789-1796.
  3. ^ a b c d J. Z. Ginos et al. (1895). "Cholinergic effects of molecular segments of apomorphine and dopaminergic effects of N,N-dialkylated dopamines." J. Med. Chem. 18 1194-1200.
  4. ^ a b R. J. Borgman, J. J. McPhillips, R. E. Stitzel, and I. J. Goodman (1973). "Synthesis and pharmacology of centrally acting dopamine derivatives and analogs in relation to Parkinson's disease." J. Med. Chem. 16 630-633.
  5. ^ J. W. Daly, C. R. Creveling, and B. Witkop (1966). "The chemorelease of norepinephrine from mouse hearts. Structure-activity relationships. I. Sympathomimetic and related amines." J. Med. Chem. 9 273-280.
  6. ^ L. I. Goldberg, P. F. Sonneville, and J. L. McNay (1968). "An investigation of the structural requirements for dopamine-like renal vasodilation: phenethylamines and apomorphine." J. Pharmacol. Exp. Ther. 163 188-197.
  7. ^ M. Ilhan, J. P. Long and J. G. Cannon (1975). "Bulbocapnine's ability to antagonize the adrenergic inhibitory action of dopamine and analogs." Eur. J. Pharmacol. 33 13-18.
  8. ^ J. M. Kitzen, M. Ilhan, J. G. Cannon and J. P. Long (1976). "α-Adrenergic activity of N,N-dimethyldopamine (DMDA)." Eur. J. Pharmacol. 38 365-372.
  9. ^ J. G. Cannon, F.-L. Hsu, J. P. Long, J. R. Flynn, B. Costall, and R. J. Naylor (1978). "Preparation and biological actions of some symmetrically N,N-disubstituted dopamines." J. Med. Chem. 21 248–253.
  10. ^ B. Costall, R. J. Naylor and R. M. Pinder (1976). "Characterisation of the mechanisms for hyperactivity induction from the nucleus accumbens by phenethylamine derivatives." Psychopharmacol. 48 225-231.
  11. ^ B. Costall, S. K. Lim, and R. J. Naylor (1981). "Characterisation of the mechanisms by which purported dopamine agonists reduce spontaneous locomotor activity of mice." Eur. J. Pharmacol. 73 175-188.
  12. ^ P. Seeman, M. Watanabe, D. Grigoriadis, J. L. Tedesco, S. R. George, U. Svensson, J. L. Nilsson, and J. L. Neumeyer (1985). "Dopamine D2 receptor binding sites for agonists. A tetrahedral model." Mol. Pharmacol. 28 391-399.
  13. ^ R. A. Wallace, T. Farooqui, L. Wallace, J. Ares, Y.A. Chang, D. Miller, and N. Uretsky (1987). "Interaction of permanently charged analogs of dopamine with the D-2 dopaminergic receptor." Biochem. Pharmacol. 36 3903 – 3910.
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