Phenylethanolamine derivatives

Imidazolines and Guanidines. Although nearly all /3-agonists are phenylethanolamine derivatives, a-adrenoceptors accommodate a far more diverse assortment of structures (80). Naphazoline (29), osgmietazoline (30),... 

Quantitative studies of ring-methylated phenylethanolamine derivatives led to precisely similar results (Misekova et dl., 1966) competitive dualism with autoinhibition in higher concentrations was found. 

Derivatives of phenylethanolamine substituted by a phenolic hydroxyl on the para position have been known for some time to exhibit 0-adrenergic agonist activity. As a consequence of this property, the compounds have proven useful as bronchodilators for the treatment of asthma (see Chapter 3). Since such sympathomimetic drugs tend to have undesired activity on the cardiovascular system in addition to the desired activity on the bronchii, considerable work has been devoted to the preparation of compounds that would show selectivity for the adrenergic receptors (02> that predominate in the lung. Attachment of the side chain to a heterocyclic aromatic phenol has been one avenue that has shown promise for achieving this selectivity. 

A related scheme starts with the conversion of the exocyclic amino group in 2-methylaminoimidazohne to a good leaving group by conversion to its nitramine derivative (5-2). Reaction of that intermediate with phenylethanolamine (5-1) leads to the displacement of the nitramine by the primary amine on the reagent and the formation of the substitution product (5-3). This is then cyclized with concentrated sulfuric acid to give an imidazoimidazole, probably via the benzylic carbocation. There is thus obtained imafen (5-4) [5], a compound described as an antidepressant. 

Pentryl, or 2,4,6-trinitrophenyInitraminoethyI nitrate, is another explosive which is derived from ethylene. It is a nitric ester, an aromatic nitro compound, and a nitroamine. The substance was described in 1925 by Moran54 who prepared it by the action of mixed acid on 2,4-dinitrophenylethanolamine (large orange-yellow crystals from alcohol, m.p. 92°) procured by the interaction of dinitrochlorobenzene with ethanolamine. von Herz later prepared pentryl by the nitration of 0-hydroxyethylaniline, a material which is more commonly called phenylethanolamine and is now available commercially in this country, and was granted... 

Three chiral stationary phases that were prepared by derivatizing y-mercaptopropylsilanized silica gel with quinine (CSP II), quinidine (CSP III), and cinchonidine (CSP IV), have been used for the successful resolution of N-acyl derivatives of fl-hydroxyphenethylamines [25]. UV and CD detectors set at 270 nm were used in series. The effectiveness of the separation and the detection are illustrated in Figure 6 for the resolution of the N-(3,5-dinitrobenzoyl) derivative of phenylethanolamine on CSP III. 

Figure 6. The resolution of N-(3,5-dinitrobenzoyl) derivative of phenylethanolamine on the CSP III. Eluant is hexane/2-propoanol/acetonitrile, 80/20/5 (v/v/v). Absorption (A) and CD (0) detection at 270nm. (From Ref. 24).

However, because phenylethanolamine-N-methyl-transferase (PNMT) is expressed mainly in adrenal chromaffin cells, more than 90% of circulating epinephrine is derived from the adrenal meduUa. This contrasts with... 

The enzymes involved in the formation of the catecholamines are of low specificity. DOPA decarboxylase, or an enzyme closely akin to it, is concerned in the formation of 5-hydroxytryptamine > dopamine-/9-oxidase has been shown to be capable of hydroxylating the jd-carbon atom of a number of tyramine derivatives - and phenylethanolamine A-methyltransferase is equally unselective in its A-methylation of noradrenaline derivatives . This lack of specificity suggests the possibility that alternative pathways for the formation of noradrenaline and adrenaline might exist in vivo. Some of the putative intermediaries in these other pathways have been shown to occur naturally and one of them, octopamine (/) is found in the brain . 

Norepinephrine is biosynthesized in the neurons of both the central nervous system and the autonomio nervous system, whereas EPI is formed in the ohromaffin cells of the adrenal medulla. Both NE and EPI are derived from L-tyrosine by a series of enzyme-catalyzed reactions (Fig. 44.4 depicts the overall pathway). L-Tyrosine hydroxylase hydroxylates the meta position of L-tyrosine, producing L-dihydroxyphenylalanine (L-DOPA) and is the rate-limiting step. The L-DOPA is then decarboxylated by L-aromatic amino acid decarboxylase to form dopamine, which is converted to NE by the action of dopamine p-hydroxylase. Dopamine p-hydroxylase occurs in storage vesicles of the nerve ending, and the NE formed is stored there until it is released into the synaptic cleft. In the chromaffin cells, the formed NE is converted to EPI by N-methylation catalyzed by phenylethanolamine N-methyltransferase. 

In adrenal and extramedullary chromaflBn cells NA may be further converted to ADR by this enzyme. The partially purified enzyme from monkey adrenal glands requires S-adenosyl methionine as methyl donor, and will N-methylate a variety of -phenylethanolamines. -phenylethylamines do not serve as substrates but may act as competitive inhibitors. The enzyme is not absolutely stereospecific for L-NA, but also acts on D-NA with lower affinity. ADR and related secondary amines can be further converted to the respective N-dimethyl derivatives by the enzyme. Small amounts of N-dimethyl NA occur naturally in the adrenal medulla. 

In addition to amino acids, a number of phenylethylamine derivatives are taken up by adrenergic nerves and converted by dopamine- -hydroxylase into the corresponding ) -hydroxylated phenylethanolamines. which may then be stored and released (Fig. 12). In addition some phenylethylamines may first be ring hydroxyl-ated by a liver microsomal system, the resulting products taken up into adrenergic nerves and -hydroxylated. This occurs, for example, with amphetamine, which gives rise in certain species to the amines norephedrine and p-hydroxynorq>hedrine which are retained in the tissue stores (Fig. 12). 

Chemically bonded CSPs based on (18-crown-6) 2,3,1142-tetracarboxylic acid (ISCeTA, Fig. 10) are highly effective in the resolution of natural and unnatural a-amino acids (except for proline) [131-133], primary and secondary amino alcohols [134-136], P-amino acids [137], aryl a-amino ketone [138], and a-amino acid derivatives [20, 131], A number of pharmaceutically important compounds such as P-blockers [134, 135], fluoroquinolone antibacterial agents [139], amphetamine, phenylethanolamine, octopamine, and norepinephrine [132] were separated quite well on this crown ether CSP. 

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