Aporphines pharmacology

In Malaysia, a paste of leaves is applied to sore legs, and a decoction of the leaves is drunk as a protective remedy given after childbirth. To date, the pharmacological potential of F. fulgens (Hk. f. et Th.) Merr. is unexplored. It would be interesting to learn whether further study on this medicinal plant disclose any aporphines of chemotherapeutic interest. 

The plant is used by Malays to assuage body pains, and a decoction of roots is drunk as a protective remedy after childbirth. The pharmacological properties of this plant are unknown, but it is very probable that it elaborates aporphines and flavonoids as characterized in Oxymitra velutina (5). 

Microbial formation of plant isoquinolines became an attractive issue over recent years [116]. Magnoflorine was of particular interest thanks to its pharmacological activities. On one hand, it was found that this aporphine alkaloid protects human high density lipoprotein (HDL) against lipid peroxidation but it also exhibits anti-HIV activity [117-119]. New production strategies for this alkaloid will be vital in the future. 

The alkaloids corydine, bulbocapnine, and isocorydine have an adrenolytic effect (427, 428). All of them, including glaucine, act cholinergically (429, 430) this effect is, however, smaller than that of dehydrocholic acid. For the synthesis and pharmacology of aporphine, the pharmacology of (— )-nornuciferine and of pukateine, see Kupchan, et al. (379), Weisbach et al. (431), and Smith et al. (432, 433), Burkman and Cannon (434), and Fogg (435). 

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. 

These domino reactions have also been employed by us for the total synthesis of pharmacologically important [50,51] aporphine alkaloids namely dehydronomuciferine (1) and ( ) N-nomuciferine (2)(Scheme 1), and biologically active [52] phenanthrene alkaloids namely N-noratherosperminine (3) and atherosperminine (4)(Scheme 2). Incidentally, phenanthrene alkaloids are related to the aporphines, from which they can be obtained by degradative procedures [37],... 

Pharmacological studies on aporphines have centred mainly around (—)-apomorphine (41) and its close relatives because this degradation product of morphine stimulates the dopaminergic system in rats and mice, and has anti-Parkinson activity. It also has a hypotensive effect and very recently has been shown... 

The metabolism of apocodeine to apomorphine and norapomorphine was shown to occur in rats. The clinical application of apomorphine has been discussed. The synthesis and pharmacological testing of several aporphine alkaloid analogues have been reported. The pharmacology of liriodenine, thalicminine, corydine, and isocorydine hydrochloride has been investigated. The synthesis of tritium- and deuterium-labelled apomorphine has been reported. " Under controlled conditions, exclusive introduction of label into the catechol ring of the molecule was achieved. 

Cannon, J.G. Moe, S.T. Long J.P. Enantiomers of 11-hydroxy-10-methyl-aporphine having opposing pharmacological effects at 5-HTia receptors. Chirality 1991, 3, 19-23. 

A number of aporphine alkaloids have been isolated in this laboratory in such small quantities that their structure could at first only be stablished on the basis of their spectroscopic characteristics (Ref. 1). The need to confirm the structures of these new alkaloids and to obtain them in quantities sufficient to allow investigation of their pharmacological properties led us to attempt their synthesis by classical methods, but the problems encountered in some cases forced us to try modified or radically different approaches. As a result, we have developed a new synthetic procedure that is applicable to a variety of different kinds of isoquinoline alkaloids. 

Berezhinskaya VV, Aleshinskaya EE, Aleskina YaA (1968) Comparative pharmacological study of some alkaloids of aporphine group. Farmakol Toksikol 31(l) 44-46 (in Russian)... 

The pharmacological activity of certain bisbenzylisoqui-noline alkaloids has been reviewed (Buck, 1987 Schiff, 1987). Many of these compounds have weak to moderate antimicrobial activity. Two types of bisisoquinoline alkaloids possess antitumor activity. These are bisbenzylisoqui-noline and aporphine-benzylisoquinoline alkaloids [e.g., tetrandrine (99) and thalicarpine (100), respectively]. Both have pronounced side effects (Cordell, 1978b). 

For the synthesis and pharmacological testing of several aporphines, see F. Schneider, M. Gerold, and K. Bernauer, Helv. Chim. Acta, 56, 759 (1973). 

The known chemistry of the Annonaceae is mainly based on the work of Cave and Leboeuf on the benzyhsoquinoline alkaloids. After this work, several papers were published which evidenced the presence of alkaloids derivatives of isoquinolines. Approximately 800 alkaloids of the types isoquinolines, protoberberine, aporphine, and others were isolated from different genera of the Aimonaceae. Previous chemical and pharmacological investigations have indicated that bisbenzylisoquinolines are important bioactive components existing in plants of the Annonaceae family. Other terpenes, flavonoids, Hgnans, acetogenins, and some aromatic compounds are also found in the family but the alkaloids are the major chemical constituents. 

Introduction - Interest in the aporphine alkaloids continues at a rather high level, and a number of developments have been reported since the appearance of the last review (April, 1966) on this class of compounds-More than thirty new aporphines of varied structure have been isolated from natural sources the structures of a few members have been confirmed by total synthesis. The synthesis of aporphines by methods other than the classical Pschorr method continues to be e3q>lored, and some new ring systems related to the aporphines have been synthesized. Some new pharmacological studies employing aporphines have been reported. 

The presence of the A-ring of aporphines, and the addition of substituents to it can extend explorations of the dimensions and other characteristics of the dopamine receptor. Accordin y the synthesis of a series of (—)2,10,11-trihydroxyaporphines was undertaken and their in vivo (Neumeyer et al. 1981b) and in vitro characteristics were evaluated. The enantiomers (6aR and 6aS) of 2,10,11-trihydroxyaporphine (16a, THA) were synthesized from thebaine and bulbocapnine and evaluated pharmacologically (Neumeyer et al. 1982). The (—) 1,2,11-trihydroxyaporphine (17) was prepared from the naturally occurring aporphine alkaloid (R)-pukateine (15) using boron tribromide (Ram and Neumeyer 1984). 

---