Apomorphine, structure

The ortho diphenolic structure of apomorphine makes it a strongly reducing substance hence, in acid medium it forms the blue colored or//io-qulnone (6) with iodine or other oxidizing agent which is in equilibrium with its zwitterionic limiting structure (7) (Pellargi s reaction [14]). 

The most known narcotics are the opium alkaloids such as morphine, codeine, thebaine, papaverine, noscapine and their derivatives and modified compounds such as nalmorphine, apomorphine, apomopholcodine, dihydrocodeine, hydro-morphone and heroine, also known as diamorphine. Synthetic narcotics share the structural skeleton of morphine and include dextromethorphan, pentazocine, phenazocine meperidine (pethidine), phentanyl, anfentaitil, remifentalin, methadone, dextropropoxyphene, levoproxyphene, dipipanone, dextromoramide, meptazinol and tramadol. Thebaine derivatives are also modified narcotics and include oxycodone, oxymorphone, etorphine, buprenorphine, nalbuphine, naloxone or naltrexone. Narcotics can be semi-synthesized or totally synthesized from the morphine and thebaine model. The compounds serve various purposes in clinical practise. 

Some of the earliest and most complete efforts at structural dissection have been carried through by Cannon and his co-workers at the University of Iowa. These studies were initially directed toward elucidation of the pharmacophoric element within the structure of the emetic agent apomorphine, I. The suggestion by Pinder et al. (2) that the 5,6-dihydroxy-2-aminotetralin fragment was the active moiety was followed in short order by the report of Cannon et al. (3) that the N,N-dimethyl derivative ("M-7") II was a potent emetic in the dog. Additional pharmacology on M-7 provided by Long et al. (4) further illustrated the similarity between I and II. Both... 

Cannon, in 1975, suggested that dopamine might bind to Its receptors in two possible conformational extremes, which he designated the "alpha" and "beta" rotamers, XIa and Xlb, respectively (20). In this view apomorphine would represent a structure containing a dopamine fragment "frozen" into the alpha rotameric form. By contrast, 6,7-ADTN contains a dopamine moiety constrained in the beta rotameric form. In both cases the side chain is nearly coplanar with the aromatic ring and is... 

The importance of resolution and determination of absolute configuration cannot be overemphasized. There was, in this writer s opinion, little significant progress in developing useful receptor models prior to the determination of the absolute configurations for the active enantiomers of apomorphine, I, certain N-substituted 5-hydroxy-2-amino-l,2,3,4-tetrahydronaphthalenes, and of 6,7-ADTN (X). It is very common to see structures drawn in the literature with their chiral center shown as a particular absolute configuration, for example similar to that of apomorphine. Yet, in many of these cases there is no evidence as to which isomer is active. The reversed stereochemistry for the active enantiomers of apomorphine and... 

Fig. 4 A molecular model of the dopamine D2 receptor with a ligand docked in the binding site. The model of the D2 receptor transmembrane helices was constructed from the coordinates of the bacteriorhodopsin structure derived from two-dimensional electron diffraction experiments and is consistent with the projection structure for rhodopsin. The transmembrane helices are represented by a solid ribbon and the drug, apomorphine, is a space filling representation. The top view looking down the helical axis of the receptor clearly delineates the seven transmembrane helices that are the key structural motif for the GPCR superfamily. Some of the helices are inclined relative to the perpendicular to the membrane plane. The bottom view is in the plane of the membrane with the extracellular space at the top of the figure. (Adapted from Ref.t f)...

A range of alkaloids including isoquinoline, indolizidine, benzazepine, oxazine, quinoline and indole alkaloids were examined as potential inhibitors of eukaryote protein kinases such as PKC, MLCK and PKA. Only three oxazine alkaloids and four isoquinoline-based alkaloids and inhibitors of the protein kinases tested. A narrow structural and protein kinase target specificity, was observed. (+)-Boldine (39) and bulbocapnine (40) are specific for MLCK, while apomorphine (41) and sanguinarine (42) are for PKA. 

The change in structure from morphine to apomorphine profoundly changes its physiological action. The central depressant effects of morphine are much less pronounced, and the stimulant effects are enhanced greatly, thereby producing emesis by a purely central mechanism. It is administered subcutaneously to obtain emesis. It is ineffective orally. Apomorphine is one of the most effective, prompt (10 to 15 minutes), and safe emetics in use today. Care should be exercised in its use. however, bccau.se it may be depressant in already-depressed patients. It is currently cla.ssified as an "orphan drug" for use in Parkinson s disease. 

Chart 1.4 Chemical structures of dopamine (1), apomorphine (11) and 11-hydroxy-N- -propylnoraporphine (12). 

Chart 5.1 Chemical structures of R-(-)-apomorphine and selected analogues. 

A desoxymorphine was stated by Schryver and Lees [54] to result from the reduction of a-chloromorphide with tin and hot concentrated hydrochloric acid, but a repetition of this reaction afforded only small amounts of material of different specific rotation that does not correspond to any of the known desoxymorphines, and indeed it is doubtful whether the morphine structure would survive such treatment, as even in the a —> /3-chloromorphide conversion considerable amounts of apomorphine [lxh] are formed. Wright also reported the production of a desoxymorphine on heating bromocodide with hydrobromic acid [55-58], but nothing further is known about this. 

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