Morphine molecule

Morphine has certain undesirable side effects. Among these are respiratory depression, nausea, and vomiting, depression of the cough reflex, cardiovascular depression and hypotension, smooth muscle contraction (constipation), and histamine release (93). Morphine s onset of action, duration, and low therapeutic indices have prompted a search for a more effective opiate iv anesthetic. Extreme simplification of the complex morphine molecule has resulted in anilido —piperidines, the fentanyl class of extremely potent opiate iv anesthetics (118,119). 

This work on the modification of the morphine molecule and its pharmacological effects has attracted a good deal of attention and several interesting interim summaries and commentaries upon it have been published. ... 

More radical dissection of the morphine molecule was in progress concurrently with the work above. The chemistry of the series of analgesics that rely on an acyclic skeleton, the compounds related to methadone, is discussed earlier. Suffice it to say that this series of agents, with the possible exception of propoxyphene, seem to share abuse and addiction potential with their polycyclic counterparts. 

Examination of the morphine molecule reveals the presence of a 4-phenylpiperidine fragment within the molecule (A). It was... 

As shown previously, most strong analgesics incorporate some portion of the morphine molecule put another way, these agents... 

Further dissection of the morphine molecule showed that potent analgesics could be obtained even when one of the carbocyclic rings was omitted. One such compound, pentazocine (52), has found considerable use as an analgesic in the clinic. There is considerable evidence to indicate this drug has much less... 

Extensive molecular dissection of the morphine molecule over the past several decades led to a host of molecules which showed narcotic analgesic activity even though they possessed but faint suggestion of the structural features present in morphine itself. Thus, both cyclic molecules such as meperidine (70) and alphaprodine (71), and acyclic Compounds such as methadone (72) were found to be effective analgesics. Common features of these compounds were formalized by the Beckett-Casy rule, which states as minimal required structural features (a) an aromatic ring attached to... 

Relatively simple modifications of morphine molecules lead to the formation of a number of compounds that differ in their analgesic activity. 

Like morphine, codeine is extracted from natural opium, obtained from the poppy plant (Papaver somniferum). Only when it was first discovered and tested was codeine purified directly from opium (see Chapter 1). Today pharmaceutical-grade codeine is synthesized from morphine through the relatively simple chemical modification process of methylation, whereby CHj replaces a hydrogen atom on the morphine molecule. The chemical substitution reaction that takes place (H for CHj) does so at a specific location on the morphine molecule (Figure 3.1) if the substitution were to occur elsewhere on... 

In the USA, this plan was directed from 1929-1939 by the Committee on Drug Addiction of the National Research Council (NRC) with financial support from the Rockefeller Foundation. The program consisted of modification of the morphine molecule at all accessible points and also targeted (modified) partial structures of the morphine molecule, such as phenanthrene, hydrogenated phenanthrene, isoquinoline, dibenzofuran, and carbazole. More than 150 derivatives of morphine and more than 300... 

The addition of two acetyl-ester groups to the morphine molecule produces a more lipophilic compound. Experimental evidence suggests that heroin and morphine may exert their effects via different receptor mechanisms.32 33... 

This ortho-4a attack, forming the carbon skeleton of the morphine molecule, is one that is not easily visualized by non-chemists. It requires an out-of-plane manipulation to bring the benzyl group into conjunction with the ring-juncture 4a carbon atom. The 1-benzyl-isoquinoline is shown in its conventional form on the left. To picture the attack, mentally take hold of the benzyl group and bring it back,... 

Apomorphine hydrochloride (Figure 44.2), an alkaloid obtained in the laboratory by rearrangements within the morphine molecule, is a grayish-white, glistening, light-sensitive, and air-sensitive crystalline powder, soluble in both water and alcohol in the proportions of about 1 50 it is available in small amounts in bulk and more easily as 5 mg (1/12 grain) tablets. 

Many attempts have been made to modify the morphine molecule or break it down to some constituent that might retain its analgesic action without its tendency to develop tolerance and addiction. However, only very closely related derivatives of morphine have been found to maintain its analgesic action and still retain to a considerable degree the undesirable potentiality to develop tolerance and addiction. 

Natural sources also supply basic compounds that may be modified slightly to render them more effective or less toxic. The numerous variations of the morphine molecule serve as examples here. 

The many rings of the morphine molecule include a benzene ring that fits into the receptors for the brain s own opiates (the endorphins and enkephalins). The nerve cells studded with these receptors recognize the morphine molecule by the close fit of the benzene ring and the binding of a critical nitrogen atom. Many other opioids duplicate these molecular features. 

In the 1970s, researchers were able to discover exactly how morphine works in the brain. When stimulated by tiny electric currents, certain nerve tracts within the core of the brain can produce a painkiller strong enough to allow abdominal surgery in lab rodents. The painkiller consists of simple amino acids that, in their naturally folded state, mimic the structure of the morphine molecule. They were named enkephalins, for in the head, and endorphins, for the morphine within. ... 

The morphine molecule possesses five asymmetric centers at carbons 5(R), 6(S), 9(R), 13(5), and 14(1 ), and it is this geometry that affords the familiar opioid pharmacological actions. The C-9 to C-13 ethanamino bridge restricts the number of possible optical isomers to 16 (i.e., eight racemic pairs). 

Modifications elsewhere in the morphine molecule including the introduction of 14-OH will be considered later (p. 54 and Chapter 12). 

In the original paper the proposition was made that the receptor of Fig. 13.4, formulated on the basis of the morphine molecule, was capable of accommodating other structural types of analgesic, and a common mode of drug-receptor interaction for both cyclic and acyclic analgesic molecules was implied. These aspects are now examined in the light of the more extensive evidence and data now available. 

Fig. 14.2. Available positions for linking morphine to a carrier protein. Depending on which position is used for conjugation different sides of the morphine molecule are exposed to the immune system.

Modirications of the morphine molecule are considered under the following headings ... 

Research initiated by Eisleb and Sehaumann in 1938. witli their discovery of the potent analgesic action of meperidine, a compound that departs radically Oom the typical morphine molecule... 

The second pha.se of the studies" dealt with the attempted synthesis of substances with central narcotic and, especially, analge.sic action. The morphine molecule contains certain well-defined types of chemical. structures. Among these are the phenanthrene nucleus, the diben/ofuran nucleus, and. as a variant of the latter, carbazolc. Thc.se. synthetic. studies, although extensive and interesting, provided no significant lindings and are not discussed further in this text. 

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