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4 Structure–Activity Relationship of Morphine and its Analogs

4 Structure–Activity Relationship of Morphine and its Analogs

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6.4 Structure---Activity Relationship of Morphine and its Analogs



O



O



H



N



H



HO



75

3-deoxymorphine



N



76

3,6-dideoxymorphine



Figure 6.9 Deoxy morphinans.



hydroxyl group generally decreases the analgesic activity, although heroin showed

higher activity. Reductive elimination of phenolic and C6 hydroxyl groups in

morphine gave 3-deoxy (75) and 3,6-dideoxy (76) morphine derivatives; the former

was found to have 1/3 the analgesic potency and showed 1/30 the receptor binding

affinity compared to morphine, whereas the latter showed same potency as

morphine and 1/3 the receptor binding affinity. These studies demonstrated that

the phenolic hydroxyl group is not essential for analgesic activity [104,105]

(Figure 6.9).

Most of codeine is metabolized to the glucuronidated form in the liver and the

remainder ($10%) is O-demethylated to morphine [106]. The enzyme that

catalyzes the demethylation of codeine to morphine is cytochrome P-450 2D6

[107]. Thus, codeine can be viewed as a prodrug of morphine. When codeine is

injected directly to the brain, it does not show any analgesic activity. This

observation proved the theory of demethylation of codeine to morphine during the

first-pass metabolism.

The activities of drugs also depend on their pharmacodynamic properties as well

as their affinity toward receptors. 6-Acetyl morphine (77, Scheme 6.13) is known as

equipotent to morphine because the acetyl group is hydrolyzed in the plasma

before it enters the central nervous system (CNS) [108]. It is four times more active

than morphine and twice as active as heroin. Its less polar nature helps it to cross

the blood–brain barrier more easily. The free phenolic group helps 6-acetyl

morphine to interact rapidly with the receptors. Heroin is the least polar, therefore

most efficient, in crossing the blood–brain barrier, but the acetyl group of the

phenol need to be removed to interact with the receptor site. Therefore, it is

less active than 6-acetyl morphine. In the case of morphine, more polar groups

reduce the concentration of the drug reaching the receptor site, hence less potent

than the previously mentioned analogs. The oxidation of the 6-hydroxyl group of

morphine to ketone in the presence of 7,8-olefin resulted in reduced activity.

However, the oxidation of the saturated compound dihydromorphine resulted in

higher activity, almost 10 times that of morphine (Scheme 6.13).

Replacement of the methyl group at the nitrogen in morphine alters the SAR

quantitatively and qualitatively. The presence of a tertiary amine in morphine

showed optimal activity. Replacement of the N-methyl group of morphine with

hydrogen reduced the activity considerably. It can be explained on the basis of

a more polar, secondary amine, which has more difficulty in crossing the



241



242



6 A Short History of the Discovery and Development of Naltrexone and Other Morphine Derivatives



HO



HO

hydrolysis



O



H



O



N



AcO



HO

77



HO



N



1



HO

oxidation



O



H



O



N



H

O



HO

1



N



8

7



78

resulted in reduced activity

HO



HO

oxidation



O



H

HO



H



12



O



N



H



N



O



79

resulted in increased activity



Scheme 6.13 Examples of morphinan derivatives and changes in their activities.



blood–brain barrier. Different substituents on nitrogen produced a wide range of

pharmacological profiles. Depending on the chain length of the nitrogen substituent, derivatives showed mixed agonist–antagonist activity [109]. Removal of the

ether bridge gives rise to morphinans, which show higher activity and long duration

of action, but are associated with higher toxicity and dependence. More interestingly,

SAR studies in morphinan analogs showed similar results to morphine, which

proved that they are binding to the same receptor site. Benzomorphans followed the

same trend and showed that the functionalization of C and D rings is not essential

for analgesic activity.

The stereochemistry of morphine also plays an important role in its activity. The

enantiomer of naturally occurring morphine did not show any activity [2]. It can be

easily explained by considering the interactions with receptor binding sites.

Natural morphine can interact with three binding sites in the receptor; however,

only one interaction is possible in the enantiomer because of its orientation (see

Figure 6.10). This explains the poor analgesic effect of unnatural morphine. This

model also explains that changes in stereochemistry even in a single chiral center

(epimer) can make drastic changes in the activity of the drug. The C14 epimer

showed only 10% activity of morphine [110].

Introduction of hydroxyl group at the C14 position showed increase in activity. It

is possible to have a hydrogen bond interaction between the amino acid residue on



6.4 Structure---Activity Relationship of Morphine and its Analogs



H

HO



binding site for

tertiary amine



no binding



H



H

N



H

OH



N



O



O



HO



OH



binding site for

aromatic ring



binding site for

phenolic hydroxyl



binding site for

aromatic ring



no binding

(-) morphine (1)



(+) morphine (2)



Figure 6.10 Receptor binding interactions for natural and unnatural morphine.



the receptor. The same hydroxyl group can create a steric strain with the

substituents on the nitrogen atom and direct them to a specific orientation to

generate agonist–antagonist activity.

The presence of a positively charged nitrogen atom was believed to be a

requirement for the interaction with the opioid receptor [111]. This cationic charge

in the opiate is assumed to interact with the carboxyl group of an aspartate residue

located in transmembrane III of the opioid receptor [112,113]. However, salvinorin

A (80), a non-nitrogenous neoclerodane diterpene, showed k-opioid agonist activity

[114,115]. The acetyl group of salvinorin A was found to be necessary for its

selectivity and affinity for the k-opioid receptor [116]. Introduction of a benzoate

group instead of the acetyl group produced first a non-nitrogenous m-opioid agonist

(81) [117]. Another analog (82) of salvinorin A, which is epimeric at C2 position,

showed d-opioid antagonist activity [118] (Figure 6.11).

Some reviews on the synthesis of morphine and congeners also address the

preparation of unnatural derivatives [119,3c]. The most recent paper reported the

O



O

O

O



2



O



H



H



O



O



Ph



O



H



80

Salvinorin A



H



O



O

O



O



H



H



O

O



O



O

O



O



O



O



1



243



O



O



81



O



O



82



Figure 6.11 Non-nitrogenous k-opioid receptor agonist salvinorin A and its analogs with different

selectivity.



244



6 A Short History of the Discovery and Development of Naltrexone and Other Morphine Derivatives



O



O



O



O



O



O



H

O



O



H



O



S



H

O



O

83a



O



83b



83c



S



O



H



SO2



O

83d



Figure 6.12 Heteroatom analogues of hydrocodone.



synthesis and biological evaluation of heteroatom analogues of hydrocodone such

as compounds 83a-d [120]. Surprisingly, only the sulfone 83d showed any activity

toward the “m” receptor binding.



6.5

Conclusions and Outlook



Semisynthetic and synthetic drugs related to morphine remain the largest class of

drugs prescribed as analgesics. Illicit use of these drugs raises serious questions

about their acceptance. Many antagonist drugs are effective against some addiction

profiles. The search is still on for an ideal analgesic (one with high potency, no side

effects, and tolerance). We hope that new research endeavors will produce the ideal

analgesic.



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7

Lincosamide Antibacterials

Hardwin O’Dowd, Alice L. Erwin, and Jason G. Lewis



7.1

Introduction



Lincomycin (1) (Figure 7.1) was discovered in the early 1960s, toward the end of

what has been termed the “Golden Age” of antibacterial drug discovery [1]. It was

isolated from an actinomycete, Streptomyces lincolnensis, by scientists at Upjohn [2].

The structure was determined to consist of a methyl thioglycoside of the first

aminodeoxy octose ever found in nature [3] (methylthiolincosaminide, MTL, 2)

appended with a 40 -propyl-substituted N-methyl proline amino acid (propylhygric

acid, 3) [4]. Lincomycin is the first example of a class of antibacterials that have

been named as “lincosamides.” Biosynthetic studies have revealed that the amino

acid moiety arises from the bioconversion of L-tyrosine [5] while the methylthiolincosaminide is derived from D-glucose [6] via several biotransformations that

are currently only partially characterized and the subject of contemporary

investigation [7]. The antibacterial spectrum covers most Gram-positive pathogens and some anaerobes. The mechanism of action was determined to be

inhibition of bacterial protein synthesis [8]. Lincomycin is typically formulated

as the hydrochloride salt and can be administered orally, or injected either

intravenously or intramuscularly.

Following the discovery of lincomycin, Upjohn embarked upon a medicinal

chemistry program that resulted in the identification of clindamycin (4)

(Figure 7.2), a semisynthetic derivative where the C7 hydroxyl group is displaced

by a chlorine atom [9]. The synthetic route proceeds directly from lincomycin, via

selective deoxychlorination at C7 using either thionyl chloride or a Vilsmeier-type

reagent [10] and does not require any protecting group manipulations. This single

atom substitution significantly improves the overall profile of the drug. The key

advantages include improved antimicrobial potency and enhanced oral bioavailability. Clindamycin rapidly supplanted lincomycin in the clinic due to its improved

profile. Two prodrugs of clindamycin were also developed, both esters at the

2-position of the lincosaminide sugar [11]. The phosphate ester prodrug [12] (5) was

initially developed for parenteral administration [13], the phosphate causing less

irritation at the site of injection than clindamycin hydrochloride. Clindamycin

Natural Products in Medicinal Chemistry, First Edition. Edited by Stephen Hanessian.

Ó 2014 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2014 by Wiley-VCH Verlag GmbH & Co. KGaA.



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