Morphine type alkaloids

Of general importance in the area of benzylisoquinoline alkaloids is a recent controversy which has arisen as a result of the proposal that alcohol addiction may involve specific biochemical events which lead to morphine-type alkaloids.54... 

Morphine has an LD50 i.v. in mouse of 226-318 mg/kg (Wink, 1993). Codeine (62) is also an important analgetic and antitussive drug. Codeine is the most widely used morphine type alkaloid it has an LD50 i.p. in mouse of 300 mg/kg (Wink, 1993). This alkaloid is derived from opium (0.2-0.7%) and synthesized by methylation of morphine (Tyler et al, 1981). Heroin (65) (Fig. 32.21), a synthetic diacetate of morphine, crosses the blood-brain barrier more rapidly than morphine and is highly euphoric and analgetic. 

If the union occurs in a position already bearing a substituent, loss of hydrogen is impossible except by migration and a morphine type of alkaloid is formed. 

A total of more than 20 total syntheses have been described which aim to generate the most important members of the morphinan-type alkaloids, morphine and codeine. These long-standing efforts in alkaloid synthesis have been primarily due to the exceptional pharmacological importance of both compounds, as the most efficacious therapies for pain and cough, respectively. 

The role of reticuline as an intermediate in the biosynthesis of the mor-phinan alkaloids (Fig. 2.8) was demonstrated by the isolation both of (S)-and (f )-reticuline from the opium poppy. An excess of the (S)-reticuline over the (f )-isomer was found in opium (poppy latex) obtained from the mature plant, in contrast to the roughly equal amounts of these two isomers that occur in poppy seedlings. Both isomers were found to be incorporated into morphine, the major alkaloid isolated from opium, although incorporation of the (f )-isomer was slightly more efficient. (f )-Reticuline is firmly established in P. somniferum as the precursor of the morphinan-type alkaloids (Loefer and Zenk, 1990). (S)-Reticuline, however, is the central intermediate in isoquinoline alkaloid biosynthesis. It has been postulated that (R)-reticuline is formed from (S)-reticuline by isomerization. This inversion of configuration can be explained by the intermediate formation of the 1,2-dehydroreticulinium ion originating from (S)-reticuline, followed by stereospecific reduction to yield the (R) counterpart. The 1,2-dehydroreticulinium ion is efficiently incorporated into opium alkaloids and its role as a precursor of the morphinan-t)q)e alkaloids has been unequivocally established (De-Eknamkul and Zenk, 1990, 1992). 

Two basic types of structures arc recognized among the opium alkaloids, the plmnanthreite (morphine) type and the benzylisoqtiinoline (papaverine) type (.see structures). 

Sinomenine, discovered by Ishiwari in Smomenium diversifolius [97], has been shown by the researches of Kondo [98] and particularly of Goto and his co-workers [99-100] to have the structure [nxvn] and to be the optical antipode of 7-methoxythebainone. It is readily converted into antipodes of substances obtainable from thebaine and codeine (see Chap. XXVI). Hasubanonine, an alkaloid isolated from Stephania japonica, is believed to be of the morphine type [101] (see Chap. XXVI). 

A new alkaloid, hasubanonine, believed to be of the morphine type has recently been isolated and studied. It can be degraded to a methine base, the acetolysis of which gives a trimethoxyacetoxyphenanthrene, which has been converted to the corresponding trimethoxyhydroxy- and tetramethoxyphenanthrenes. The structure of these compounds is not yet known [117], but the properties of the tetramethoxyphenanthrene differ from those of dimethylsinomenol [xcvn]. 

Attempts have also been made to cultivate such a type of P. somniferum which would contain a large quantity of morphine/codeine alkaloids in the straw (846, 847). This material can be adapted agrotechnically for an easier industrial isolation of morphinane alkaloids by the Kabay method. 

Indian opium (from Papaver somniferum) contains more than 30 different isoquinoline alkaloids (22 %), which can be divided into those of a morphine type and those ofa papaverine type (Fig. 5.49). The main alkaloids are morphine (Greek Morpheus God of dreams), arormd 12 %, and narcotine, around 5 %. The remainder comprises meconic acid (11 %), water (14 %), sulfuric and lactic acid (8%), fats, proteins, sugars and waxes (ca. 44%). [72, 81]... 

Aporphine-type alkaloids are formed by the intramoleculer oxidative coupling of the benzyhsoquinoline alkaloid, S-reticuline. Thus, from the ortho, ortho -, and ortho, para -intramolecular coupling of the biradicals formed from S-reticuline, bulbocapnine- and isoboldine-type aporphine alkaloids are formed, respectively. When para, ort/zo -intramolecular coupling of the biradicals formed from S-reticuline occurs, the morphine... 

Opitim contains 10-25% alkaloids, and the main constituent is morphine. Other than morphine, more than 25 alkaloids are known, and among them are other morphinan-type alkaloids (codeine and thebaine), benzyl-isoquinoline-type alkaloids (papaverine and noscapine), and protopine-type alkaloids (protopine). The biosynthetic precursor of all of these alkaloids is phenylalanine. 

Alkaloids of the morphinane group. If the tetrahydroisoquinoline alkaloid norlaudanosoline is written in such a way that part of the molecule is rotated around the dotted line (Fig. 280), the relationship to the morphinane-type alkaloids becomes obviously. The actual precursor of these compounds, however, is (R)-reticuline. It is probably attacked by a phenol oxidase (C 2.3.1) yielding a biradical which is stabilized by the formation of the dienone (- -)-salutaridine. After reduction of (-j-)-salutaridine closure of a new 0-heterocyclic ring results in the formation of thebaine. The alkaloids codeine and morphine are synthesized from thebaine in Papaver somniferum,... 

Morphine (5) and codeine (methylmorphine) (6), two major morphinan-type alkaloids with an isoqninoline skeleton, are extracted from opium, the dried milky sap released from the immature finits of poppies (Papaver somniferum). Morphine and codeine can interact with opioid receptors distribnted in brain tissnes and the periphery, and are most widely nsed as narcotic analgesics, with codeine also having an antitussive effect [4, 25, 32]. 

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