Apomorphine 0-methylation

On methylation apomorphine yields apo-i/i-coDEiNE (i/i-apocodeme, anocodeine, apomorphine methyl ether), CigHigOaN. C2H5. OH, crystallising in brilliant plates, m.p. 104-5-106-5°, or 122-5-124-5 dry), — 90° (EtOH), which is also produced when codeine or i/i-codeine is heated with oxalic acid or phosphoric acid. It stands in the same relation to codeine as apomorphine to morphine. 

Apo-4 -carotenal, 8-Apo-8 -carotenaI, 8-Apo-8 -carotenoic acid ethyl ester, 8-Apo-8 -carotenoic acid methyl ester, Apocodeine, Apomorphine see entries in Chapter 6. 

Grunblatt E, Mandel S, Maor G, Youdim MB. 2001. Gene e]q>ression analysis in N-methyl-4-phenyl- 1,2,3,6-tetrahydro-pyridine mice model of Parkinson s disease using cDNA microarray effect of R-apomorphine. J Neurochem 78 1. 

R. B. Smith, J. C. Glade, and D. W. Humphrey, High-performance liquid chromatographic separation of apomorphine and its o-methyl metabolites, J. Chromatogr., 772 570 (1979). 

The pharmacological properties of the natural and synthetic aporphines such as apomorphine (119, 120) have ensured the thorough investigation of the in vivo mammalian metabolism of this class of compounds. Reported reactions include glucuronidation (121), O-methylation (91,122) O-demeth-ylation (123), and N-demethylation (123). Studies in vitro with enzyme preparations and in vivo with microorganisms reveal a similar pattern of metabolism. 

In either the presence or absence of GTP, half-maximal stimulation of enzyme activity is achieved with 3 uM dopamine. Both 6,7-ADTM and epinine (K-methyl dopamine) stimulate adenylate cyclase activity to the same degree as does dopamine (Figure 8). In contrast, apomorphine is a partial agonist eliciting only 30 of the maximal effect of dopamine. The dopamine-stimulated adenylate cyclase activity is selectively blocked by cis-flupenthixol rather than the trans-isomer of this antagonist (JJL). Among the antagonists tested, the order of potency is cis-flupenthixol = fluphenazine > chlorpromazine > haloperidol > trans-flupenthixol (Table I). 

The N-demethylation of apomorphine, using methyl chloroformate followed by cleavage of the crude urethane with hydrazine, has been achieved.45 Normor-phothebaine, obtained by the rearrangement of northebaine, has been converted (in a series of steps) into a nitrogen mustard.46... 

The conversion of (—)-apomorphine into (+)-apomorphine has been achieved.56 The O-dealkylation of 10,11-dimethoxyaporphine, using sodium thioethoxide in dimethylformamide, has been reported.57 The reactions of the enamine dehydro-nuciferine with dimethyl acetylenedicarboxylate, methyl propiolate, methyl acrylate, and diethyl azodicarboxylate have been investigated, and have resulted in the preparation of a novel series of 7-substituted aporphines.58... 

They include iV- CjmethyM-phenyltetrahydropyridine (MPTP, 292), apomorphine 293, clozapin 294, mepivakain 295, hydromorfon 296, and zimelidine 297 in 50-80% yields with respect to 1 -methyl iodide and with better than 98% radiochemical purity. iV-[nC]methylketanserin 298 and -[ Cjmethyldexetimide 299 have also been synthesized by this method. 

Apomorphine was the most potent of the protein kinase inhibitors (IC50 for PKA-catalytic subunit 1 pM). However, the methylated aporphine alkaloid analogues of apomorphine such as bulbocapnine, isocorydine, glaucine and (+)-boldine were either inactive or poor inhibitors of this en2 yme. 

Bromination of codeine results in 1-bromocodeine and finally in a tribromocompound chlorination with chlorine water is more complex and gives resinous products [1, 2], Apomorphine [m] is formed by heating morphine and concentrated hydrochloric acid in a sealed tube above 100° C., and, together with methyl chloride, from codeine under the same conditions [3-6] (see Chap. XXII). When codeine is heated on the water-bath with concentrated hydrochloric acid, however, replacement of the hydroxyl group by chlorine occurs and a-chlorocodide is produced [7-8] this may be prepared in other ways from codeine and i/r-oodeine, and can be isomerized to /3-chlorocodide, available directly from the isomers of codeine. The corresponding derivatives of morphine have been prepared. Bromocodide and bromomorphide may be prepared in like manner but cannot be isomerized, and an iodocodide results from the treatment of a-chloro- or bromocodide with potassium iodide. 

The two phenolic groups differ markedly in reactivity. Methylation of apomorphine affords apomorphine-3-methyl ether, identical with apo-codeine, which on further methylation gives apomorphine-3 4-dimethyl ether [18]. A monoacetyl-derivative has also been prepared [63]. 

Dimethoxy-8-vinylphenanthrene [xlvih] is the end-product of exhaustive methylation of apomorphine dimethyl ether. It can be oxidized to the 8-carboxylic acid [xlix] [64-65], which oan be converted via the amine to 3 4 8-trimethoxyphenanthreno [l] [66], identical with an authentic spcoimon [07] (see Chap. XXII). 

The use of 2-nitrobenzyl halides in the Reissert alkylation, followed eventually by the Pschorr cyclization, has provided an attractive route to various aporphines (31). Thus this procedure had led to the synthesis of apomor-phine, ° apomorphine derivatives, atheroline, imenine, N-methyl-ovigerine, oconovine, 8-hydroxyaporphines, 10-hydroxyaporphines, ... 

Many semisynthetic derivatives are made by relatively simple modifications of morphine or thebaine. Codeine is methyhnorphine, the methyl substitution being on the phenolic hydroxyl group. Thebaine differs from morphine only in that both hydroxyl groups are methylated and that the ring has two double bonds (A , A ). Thebaine has little analgesic action but is a precursor of several important 14-OH compounds, such as oxycodone and naloxone. Certain derivatives of thebaine are more than 1000 times as potent as morphine (e.g., etorphine). Diacetylmorphine, or heroin, is made from morphine by acetylation at the 3 and 6 positions. Apomorphine, which also can be prepared from morphine, is a potent emetic and dopaminergic agonist. 

Codein is the methyl ether of morphin, or its superior homo-logue, and resembles that alkaloid in some of its reactions thus under similar circumstances both form apomorphin, and morphin may be converted into codein by the action of methyl iodid in the presence of KHO. Codein, however, only contains one OH group and forms a monoacetylic derivative with acetyl chlorid,. while morphin produces a diacetylic. 

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