Sugar Derivatives of Morphine: A New Window for the Development of Potent Anesthetic Drugs

This review provides a short account of carbohydrate derivatives of an important natural drug, morphine, along with their comparative efficacies as anesthetic agent. Sugar derivatives are found to have more prospect as anesthetic drug than morphine itself owing to their enhanced bioavailability. Synthetic schemes of these sugar derivatives and information on related patents are also included in this manuscript.


Introduction
Morphine (1) is a natural product occurring in the opium poppy Papaver somniferous and was first isolated in 1803 by the German pharmacist Friedrich Wilhelm Sertürner, who named it ''morphium,'' derived from ''Morpheus''-the Greek God of Dreams [1]. This natural product has been used as the most important pain killer over many decades (or centuries as opium) and it remains the most useful choice for treatment of moderate to severe pain, either acute or chronic [2,3]. The pharmacological properties observed for morphine, including analgesia, respiratory depression, and inhibition of gastrointestinal transit, are mediated by opioid receptors [4]. However, its use as analgesic drug has not been so much explored owing to its limited bioavailability as well as its pronounced toxicity. Therefore, it is of huge urge of scientific communities for searching morphine derivatives having greater bioavailability and of low toxicity so as to develop promising analgesic drugs. Thus structural modification (semi-synthesis) of morphine (1) is very much significant in this context.
Glycosylation of natural products in some cases is considered as an effective structural modification responsible for enhancing hydrophilicity of the molecules concerned-as a result of which pharmacokinetic and/or pharmacodynamic properties may be improved, although literature survey reveals that drugs having sugar moiety have generally less hydrophilicity compared to its non-sugar analogue. In some cases, attachment of a glycosyl residue provides a new chemical entity (prodrug), which facilitates the drug delivery in a more effective manner. It has been found that inclusion of carbohydrate moieties in a drug may increase its bioavailability and decrease toxicity. Therefore, sugar derivative of a drug may be more effective in treating a disease in such cases. We have attempted in this manuscript to focus some way-outs for searching new promising anesthetic drugs having morphine skeleton by considering different carbohydrate derivatives of morphine along with their comparative efficacies as anesthetic agent mentioning also the synthetic schemes used for their synthesis.

Synthesis of Morphine Sugar Derivatives
In order to search better anesthetic agent, many sugar derivatives of morphine (1) have been synthesized (Fig. 1).
In the following Table 1 a notable number of such sugar derivatives have been presented and their synthetic schemes have been discussed later on. A comparative discussion of sugar derivatives as anesthetic agents has been presented in the bioactivity section. Sugar derivatives of morphine are presented in the following Table 1 and corresponding synthetic schemes are given.

Biological Activities
There are three major types of opioid receptors: mu (l), delta (d) and kappa (j). Morphine (1) is an agonist and partial agonist of l and d opioid receptors, respectively [20]. Opioid receptors are mainly localized in the limbic system. They are involved in the control of emotion and reward behaviors; the ascending and descending pain pathways that include the different laminae layers of cortex, thalamus, periaqueductal grey, midbrain median raphae and the dorsal horn of the spinal cord; and specific brain regions that are known to control locomotion, emesis, cough and temperature [20]. Some pharmacological effects associated with opioid receptor types are presented in Table 2.
In human beings, morphine (1) is predominantly metabolized by hepatic glucuronosyl transferases with the addition of glucuronic acid at 3-O-position in the aromatic ring or at 6-O position on the phenanthrene ring, furnishing the morphine 3-O-glucuronide (8, M3G) and morphine 6-O-glucuronide (7, M6G), respectively [21,22]. Approximately 10 % of morphine (1) is metabolized to M6G (7) and 50 % to M3G (8) [23]. Many reports have disclosed the very low affinity of 8 to l-opioid receptors [24] and, in a small study in humans, it appeared to be devoid of significant analgesic activity [25]. However, the analgesic potency of 7 in animals with significantly reduced respiratory depression, nausea, and sedation is about 100 times  (10) 10b Scheme 6 Synthesis of 4-deoxymorphine-6-glucuronide (10) [6] greater than that of morphine [26,27]. It has been found that the high potency of M6G (7) as an analgesic is mediated through opioid receptors [28]. These observations are apparently controversial due to the polar properties of 7. Villesen et al. [29] studied pharmacokinetics of M6G (7) on healthy volunteers and proposed that M6G is hydrolysed to morphine 1 in the colon, which is then absorbed and subsequently undergoes metabolism in the liver to morphine-3-glucuronide (8, M3G) and M6G [29]. M6G (7) is also able to penetrate the blood-brain barrier, although this occurs in a lower extent when compared to morphine [30][31][32]. Two possible mechanisms for this phenomenon have been proposed. The first one lies on the active transport of M6G across blood-brain barrier through a glucose transporter. There is an evidence on modulation of M6G entry into brain by membrane P-glycoprotein (Pgp) [33][34][35]. The second hypothesis is based on partitioning experiments and computer simulations and suggests that M6G molecules act like ''molecular chameleons'' by adopting a confirmation of lower polarity when passing the blood-brain barrier (BBB) [36][37][38]. Research is going on only to include sugar moiety at 6-position and to compare their anesthetic potential with morphine in order to develop new improved anesthetic drug. Therefore, limited reports are expected. In summary, the reduction in side-effects and enhanced potency observed for M6G make this morphine glycoderivative a promising drug candidate for the treatment of cancer-related pain as well as a lead compound for further development of new drugs.
Recently, non-glucuronic analogues (2-4 and 10-11) of M6G were synthesized. Affinities of these morphine glycosides to l receptor as well as in vivo antinociceptive   (13) Morphine-N-acetic acid-6-glucuronide (15) N-Cyclopropylmetnyl M6G (16)  (14), Morphine-N-acetic acid-6-glucuronide (15) and N-cyclopropylmethyl M6G (16) [6] activities using the hotplate method were also described [6]. This study shows that b-glucoside 2 was the only compound with significant antinociceptive activity at doses of 2 and 4 mg/kg, along with slightly higher affinity for l 1 receptor. Then, the constant of receptor inhibition (ki) for compound 2 was 0.28 nM whereas morphine (1) or M6G (7) presented a ki of 0.78 and 1.5 nM, respectively. When rhamnoside substitutes glucose (analogue 4) the ki for this morphine glycoderivative towards l 1 receptor becomes 0.17 nM. However, its antinociceptive activity is very low. The galactoside 3 (ki = 1.2 nM) had similar l 1 affinity to morphine (1) and M6G (7), showing some antinociceptive activity at 4 mg/kg and significant one at 8 mg/kg. All glycoderivatives studied (2)(3)(4) presented affinity to l 2 receptor similar to that for morphine. The analogues 10 and 11, which possess acid sugar residues, showed slightly higher l 1 affinity, but reduced antinociception when compared with morphine (1) [6]. In general, Stachulski and coworkers disclosed that modification of the carbohydrate at 6-O-position of morphine promotes marked in vitro effects on binding to l opioid receptor subtypes l 1 or l 2 and in vivo antinociceptive activity [6]. 6-morphinyl-a-Dmannopyranoside (5) is found to have 100-fold higher naloxone-reversible antinociception activity and twice as long lasting compared to morphine (1) when administered intraperitoneally to rats. Moreover, this compound 5 does not produce tolerance and binds to rat l opioid receptors with two fold affinities than morphine 1. It has been concluded on the basis of NMR studies that differences of activity between the derivative and its parent compound M6G (7) might be related to their differing molecular dynamic behavior [9]. Although M6G (7) and some of its O-glycosides present significantly greater analgesic potency than morphine (1), the bioavailability of these compounds could be a problem for a useful drug. For instance, the oral bioavailability of M6G is only 11 % and improvement of chemical and metabolic stability of M6G could possibly increase its effectiveness as a potential drug. Limited hydrophilicity has been a major problem in most of the cases for morphine sugar derivatives making obstacles to be used in clinic.
However, examples are known which are in Clinical trials e.g. M6G is being developed by CeNeS (Cambridge, UK) as a treatment for postoperative pain, and is currently undergoing phase III trials in Europe, with phase III clinical trials in the USA expected to commence in 2007 [39]. A general strategy for improving in vivo metabolic stability of glycoconjugates involves the replacement of glycosidic oxygen atom by carbon, nitrogen, or sulfur atoms. Indeed, MacDougall and coworkers have developed a new series of sulfur (24a, 24b, 25a and 25c) and carbon (26 and 27) glycosides (Fig. 1)  some compounds with metabolic stability for sustained pharmacological activity [4,19]. Compounds 24a and 24b were full l receptor agonists, whereas compounds 25a and 25c were only partial agonists. This finding indicates that the presence of a hydrogen atom (as a hydrogen bound donor) or a carboxyl group at C-6 0 in sugar moiety is not a requirement for agonist activity of these analogues. Moreover, analogue 27 and its deprotected sugar congener 26 were both l receptor selective [19]. Compound 27 (ki = 0.5 nM) presented an affinity to l opioid receptor 26-fold higher than that observed for M6G. Selectivities of compound 27 for l versus d and l versus j receptors were tenfold and 34-fold, respectively. Higher potency was also observed for 26 (3.7-fold) in comparison with M6G. Selectivity of compound 26 for l versus d and l versus j receptors were 77-fold and 166-fold, respectively. This compound showed slightly greater potency towards l receptor (2.5-fold) over M6G (8) Table 3 Related patent information on morphine and its sugar derivatives

Conclusion
It may concluded from the above discussions that glycosylation of the natural product, morphine (an anesthetic drug) is responsible for the effective structural modification for enhancing hydrophilicity of the compound-as a result of which pharmacokinetic and/or pharmacodynamic properties are improved. In some cases, attachment of glycosyl residue provides a new chemical entity (prodrug), which facilitates the drug delivery in a more effective manner. A significant number of related patents have also been filed so far. Therefore, this review will be very much helpful for the direction of searching new effective anesthetic drug containing morphine skeleton in near future.