Alpha-methyl

C8H14 1-OCTYNE 79.739 5.0705E-01 4.5503E-05 235.39 372 C9H10 ALPHA-METHYL- 111.072 3.1472E-01 3.7121 E-05 208.53... 

Chemcal Designations - Synonyms Methacrylic Acid, Butyl Ester Butyl Methacrylate Butyl 2-Methacrylate n-Butyl alpha-Methyl Acrylate Butyl 2-Metiiyl-2-Propenoate Chemical Formula CHj=C(CH3)COOCH2CH2CHiCH3... 

Chemical Designations - Synonyms Glycidyl alpha-methyl acrylate Methacrylic acid, 2,3-epoxypropyl ester Chemical Formula CHj=CH(CH3)C00CH2CHCH20. 

This ester (70 g) and diethyl carbonate (250 mg) were stirred at 90°C to 100°C while a solution of sodium ethoxide [from sodium (7.8 g) and ethanol (1 54 ml)] was added over 1 hr. During addition, ethanol was allowed to distill and after addition distillation was continued until the column heat temperature reached 124°C. After cooling the solution to 90°C, dimethyl sulfate (33 ml) was followed by a further 85 ml of diethyl carbonate. This solution was stirred and refluxed for 1 hr and then, when Ice cool, was diluted with water and acetic acid (10 ml). The malonate was isolated in ether and fractionally distilled to yield a fraction boiling at 148°C to 153°C/0.075 mm, identified as the alpha-methyl malonate. This was hydrolyzed by refluxing for 1 hr at 2.5N sodium hydroxide (350 ml) and alcohol (175 ml), excess alcohol was distilled and the residual suspension of sodium salt was acidified with hydrochloric acid to give a precipitate of the alpha-methyl malonic acid. This was decarboxylated by heating at 180°C to 200°Cfor 30 minutes and recrystallized from petroleum ether (BP 80°C to 100°C) to give 2-(2-fluoro-4-biphenylyl)propionic acid, MP 110°C to 111°C. 

Extension of the alpha-methyl to an alpha-ethyl abolishes hallucinogenic activity, but has only a minor effect on entactogens. 

It could not be anticipated that the extension of the alpha-methyl of MDMA to an alpha-ethyl would also attenuate the effects of the compound on dopaminergic pathways in the brain. In contrast to MDMA, MBDB has no significant effect either on inhibition of uptake of dopamine into striatal synaptosomes (Steele et al. 1987) or on release of dopamine from caudate... 

In designing studies of the structure-activity relationships of MDMA and related substances, there are at least three areas for structural modification. First, the nature of the amine substituents can be varied other N-alkyls can be studied, or the nitrogen can be incorporated into a ring system. A second point for structural modification is the side chain. As already demonstrated, the alpha-methyl can be extended to an alpha-ethyl. Other modifications of the side chain would include incorporation into a variety of ring systems, or a,a-dialkylation. Finally, the nature and location of the ring substituents can be modified. 

I really cannot think of an enzyme system that would cleave that down to the alpha-methyl. I think the effect is due to the alpha-ethyl. 

The reinforeing properties of psychomotor stimulants have also been linked to the aetivation of eentral dopamine neurons and their postsynaptie reeep-tors. When the synthesis of eatecholamines is inhibited by administering alpha-methyl-para-tyrosine, an attenuation of the subjective effeets of euphoria assoeiated with psyehomotor stimulants oeeurs in man (Jonsson et al. 1971), and a bloekade of the reinforeing effects of methamphetamine occurs in animals (Pickens et al. 1968). Furthermore, low doses of dopamine antagonists will increase response rates for intravenous injections of h-amphetamine (Risner and Jones 1976 Yokel and Wise 1975 Yokel and Wise 1976). 

The administration of low doses of PCP to rodents induces hyperactivity and stereotypy (Chen et al. 1959 ). The observation that neuroleptics such as chlorpromazine, haloperidol, and pimozide, and adrenolytics such as alpha-methyl paratyrosine antagonize these behavioral effects of PCP suggests that they are mediated by facilitation of central dopaminergic neurotransmission (Murray and Horita 1979). The actions of PCP on central dopaminergic neurotransmission may be similar to amphetamine. A dose of PCP (2.5 mg/kg) in rats, which has no effects when given alone, enhances the behavioral effects of 1 and 3 mg/kg of d-amphetamine (Balster and Chait 1978). PCP, like dopamine, has also been shown to suppress plasma prolactin (Bayorh et al. 1983). However, the firm establishment of an excl usive relationship between dopamine neuro-transmission and PCP effects is difficult because of the prominent interactions of this drug with other neurotransmitter systems. 

J. J. Grimaldi, B. D. Sykes 1975, (Con-canavalin A a stopped flow nuclear magnetic resonance study of conformational changes induced by Mn++, Ca++, and alpha-methyl-D-mannoside),/. Biol. Chem. 250, 1618. 

ALPHA-METHYL STYRENE ETHYL BENZOATE N-PROPYLBENZENE ISOPROPYLBENZENE l-METHYL-2-ETHYLBENZENE... 

Dialkyl substitution on the alpha-carbon also abolishes activity, the a,a-dimethyl analog of DOM, Structure 10, is inactive in a variety of assays (10). Linking the two alpha-methyls to give the cyclopropyl analog Structure 11 restores activity in a cat behavioral model (10). The difference in activity between 10 and 11 has been ascribed to the inability of 10 to adopt an antiperiplanar... 

Alpha-methylation of DMT reduced its behavioral activity in animals, while alpha-methylation of N-methyltryptamine (27) resulted in an agent with stimulant properties (137,228). Alpha-methyltryptamine (a-MeT structure 77), however, is hallucinogenic in man at doses of about 30 mg. Thus it is two to three times more active than DMT (for review see refs. 24, 81, and 196). 5-Methoxy-a-methyltryptamine (5-OMe-a-MeT 78) was also determined to be twice as active in man as its dialkyl counterpart, 5-OMeDMT. In human trials, 5-OMe-a-MeT produced behavioral effects at about 3 mg (204). A comparison of the activities of the individual isomers of 78 in man has not been reported. However, Glennon and co-workers (76,83,90) found that the (+)-isomers of both a-MeT and 5-OMe-a-MeT are more active than their racemates in tests of discriminative control of behavior in rats. Although (+)-5-OMe-a-MeT was four times more active than its enantiomer, (-)-a-MeT did not produce effects similar to either racemic a-MeT or 5-OMeDMT. 

Taken together, the data presented here show that many phenyl- and in-dolealkylamines are hallucinogenic in man and behaviorally active in animals. In both series, primary amines penetrate the blood-brain barrier with difficulty, although this seems to be more of a problem with tryptamines (and even N-monoalkyltryptamines) than with phenethylamines. This situation is somewhat alleviated in the presence of an alpha-methyl substituent. The primary amines are also prone to rapid metabolism by oxidative deamination. Metabolism, however, can be impeded by the presence of an alpha-methyl or N-alkyl function. 

Appel, J. B., Lovell, R. A., and Freedman, D. X. (1970) Alterations in the behavioral effects of lysergic acid diethylamide by pre-treatment with p-chlorophenylalanine and alpha-methyl-... 

While mescaline is a simple 2-phenethylamine derivative, the addition of an alpha-methyl group to the side chain yields Structure 8 (TMA). This simple hybrid of the structures of mescaline and amphetamine retains the hallucinogenic effects of mescaline but possesses about twice the potency of the latter (174,200). Addition of the alpha-methyl to other 3,4,5-substituted compounds generally brings about an approximately twofold increase in potency. The addition of an alpha-methyl to 2,4,5-substituted compounds, however, may dramatically increase activity. For example, 2-(2,4,5-trimethoxyphenyl) ethylamine apparently is clinically inactive (195). Addition of an alpha-methyl gives TMA-2 (Table 1), with 20 times the potency of mescaline. However, the addition of an alpha-methyl does not significantly increase in vitro receptor affinity in either 3,4,5-or 2,4,5-series (72,78). Thus it is probable that the alpha-methyl may confer metabolic stability in vivo. It could also be speculated that this protection is more important in the 2,4,5-substituted series than in 3,4,5-substituted compounds. 

Little work has been done in this area. Clark et al. (36), however, reported that mescaline is more extensively deaminated by a soluble rabbit liver amine oxidase preparation than is 2,4,5-trimethoxyphenethylamine. One should also note that the addition of the alpha-methyl will increase the octanol-water partition... 

Adding the second alpha-methyl to MDA gives a compound that apparently is only weakly active in man (199). Again, the 3,4-methylenedioxy substitution seems anomalous. This may also be due to an indirect effect, such as release of endogenous neurotransmitter from nerve terminals. However, neither this a,a-dimethylated MDA analog nor a,a-dimethyl-4-methoxy-/3-phenethylamine had any ability to induce the release of 3H-serotonin from rat whole brain synaptosomes (160). 

This view offers an explanation for the stereoselectivity of the phenylisopro-pylamines, i.e., the isomer that is more active is the one that presents least interference to the drug-receptor interaction. This idea would be consistent with the observation that the R enantiomers of the phenylisopropylamines have receptor affinity similar to their nonalpha-methylated homologs, and that the alpha-methyl of the S enantiomer of the amphetamines has a deleterious effect on affinity (72,78). There is no strongly compelling evidence in favor of either of the above hypotheses, however, and either is tenable. 

Both shortening and lengthening of the alkyl side chain result in decreased activity. While alpha-methylation of N,N-dialkyltryptamines reduces activity, alpha-methylation of the primary amines results in agents that are more active than their corresponding N,N-dimethyl counterparts. Further homologation of the alpha-methyl group decreases activity. 

A (Alternative) JCS 3175(1952). 2 g 3-indolyl-acetic acid (preparation given elsewhere here), 1.55 g freshly fused sodium acetate, 5 ml acetic anhydride. Heat 135-140° on oil bath for eighteen hours cool, wash with water and extract with CHCl3-ether (1 4). Wash organic phase with 3X20 ml saturated KHC03 and dry, evaporate in vacuum to get the l-acetyl-3-indolyl-acetone, which can be reduced to the alpha-methyl-tryptophol derivative with lithium aluminum hydride, and then converted to the dialkyl-tryptamine as already described (as can (I)), or used in step B, or reduced to (I) as follows dissolve 1 g in 1 ml 1 N Na-methoxide in methanol and 60 ml methanol, and keep at 40° for 10 minutes acidify with dilute HC1 and extract with ether. Dry, evaporate in vacuum to get (I) (recrystallize-methanol). 

To 123 g p-anisidine (p-methoxy-aniline) in 1 L 15% HCI add 1 Kg ice and while stirring, quickly add dropwise below the surface, a solution of 75 g NaN02 in 200 mi water (temperature below 5°). Add 5 g activated carbon, stir and filter and quickly add filtrate with stirring to a mix of 160 g ethyl-alpha-methyl-acetoacetate in 1 L methanol, 1 Kg ice and 820 g Na acetate. Stir two hours and extract with 4X500 ml benzene. Wash extract with water, dry and... 

In 1979-1980, some illegal fentanyl analogues appeared that were being sold as substitutes for heroin on the street. Suddenly, a series of more than a dozen mysterious deaths occurred in southern California. Upon autopsy, the victims strongly looked as if they had overdosed on heroin however, no traces of heroin could be found in their bodies. Later, forensic chemists identified a fentanyl analogue (alpha-methyl-fentanyl) that was present in all of the victims. As it turns out, alpha-methyl-fentanyl was being sold on the streets under the name China White (Figure 7.2), because it resembled (and contained) pure synthetic heroin that was produced in Southeast Asia. 

Figure 7.3 The chemical structure of fentanyl and its illegal analogues alpha-methyl-fentanyl and 3-methyl-fentanyl are shown here. Fentanyl was originally designed and marketed as an anesthetic, as it is 100 times stronger than morphine.

FPWSPXG Sterol 4-alpha-methyl-oxidase 1/223-2 3IArabidopsis thalianalS6% 0.2... 

The effluent from the acid treatment reactor is about 60% phenol, 35% acetone, plus some miscellaneous nits and lice, most of which, are alpha-methyl styrene, and acetophenone. The effluent is passed through a separator where the acid, water, and salts drop out. The balance of the processing is a series of distillation columns that split out the various streams. 

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