Dynamic medicinal chemistry in the elaboration of morphine-6-glucuronide analogs.

This review discusses the role of dynamic medicinal chemistry in the design and development of more effective opioids for the treatment of pain. Human Phase II clinical studies have shown that morphine-6-glucuronide (M6G) has equivalent analgesic effects to morphine and an improved side effect profile particularly at reducing the tendency to cause nausea, vomiting, sedation and respiratory depression. Based on these clinical observations, a new class of pain medication could be developed. Despite the promise, M6G is not an ideal drug because bioavailability is low and hydrolysis occurs in the gut. The literature covered includes a comprehensive list of work that illustrates: (i) the role of drug metabolism and drug disposition concepts in M6G analog drug development, (ii) the use of dynamic medicinal chemistry in improving M6G pharmaceutical properties, and (iii) the role of drug metabolism in enhancing bioavailability of M6G. Using optimized dynamic medicinal chemistry procedures for drug design and development, understanding the use of drug development concepts in early drug development and applying new methods from other fields may help advance this field of drug development. This review summarizes studies that support the feasibility of elaborating longer-acting, less expensive pain medications with possibly a safer profile of side effects. Development of new pain medications for cancer and other diseases based on M6G could provide novel agents that could balance optimal analgesia with a decreased occurrence of adverse side effects.

Synthesis and in vitro biological evaluation of a carbon glycoside analogue of morphine-6-glucuronide.

Attachment of a glucose moiety to 6-beta-aminomorphine afforded compound 3, where the glucose moiety was linked to the C-6 nitrogen atom by a two-carbon bridge. The synthesis of 3 was accomplished in eight steps from 3-triisopropylsilyl-6-beta-aminomorphine and 2,3,4,6-tetra-O-benzyl-D-glucose. The C-glycoside 3 was prepared with the objective of examining a metabolically stable analogue of morphine-6-glucuronide and determining the potency and selectivity of opioid receptor binding. Competition binding assays showed that 3 bound to the mu opioid receptor with a Ki value of 3.5 nM. The C-glycoside 3 exhibited delta/mu and kappa/mu selectivity ratios of 76 and 165, respectively. The synthetic intermediate (i.e., benzyl precursor, compound 11) bound to the mu opioid receptor with a Ki value of 0.5 nM, was less selective for the mu opioid receptor. The [35S]GTPgammaS assay was used to evaluate the functional properties of compounds 3 and 11. Compound 3 was determined to be a full agonist at the mu opioid receptor, whereas compound 11 was found to be a partial agonist. Compound 3 was determined to be very stable in the presence of human liver S9, and rat and monkey liver microsomes: no detectable loss of 3 was observed up to 90 min. Compound 3 was also very stable at pH 2 and pH 7.4, suggesting that 3 possessed properties for sustained duration of action.

Synthesis and biological evaluation of some 6-arylamidomorphines as analogues of morphine-6-glucuronide.

A series of 6-beta-arylamidomorphines was synthesized and biologically evaluated. Various aryl substituents were introduced into the arylamidomorphines to examine substituent structure-activity relationships. Competition binding assays showed that compounds 10a-h bound to the mu opioid receptor with high affinity (0.2-0.6 nM). Functional assays showed that compounds 10a-h acted as full mu opioid receptor agonists. The ED(50) of compound 10e.HCl as an analgesic was 12.6 mg/kg in the tail flick latency test in the rat.

Design, chemical synthesis, and biological evaluation of thiosaccharide analogues of morphine- and codeine-6-glucuronide.

A series of 6-beta-thiosaccharide analogues of morphine-6-glucuronide (M6G) and codeine-6-glucuronide (C6G) were synthesized and evaluated with the objective of preparing an analogue of M6G with improved biological activity. The affinity of the thiosaccharide analogues of M6G and C6G was examined by competitive binding assays at mu, delta, and kappa opioid receptors. The thiosaccharide compounds in the morphine series 5b, 5e, 6a, and 6c showed 1.5-2.4-fold higher affinity for the mu receptor than M6G, but were generally less selective than M6G. The functional activity of the M6G and C6G analogues was examined with the [35S]GTP-gamma-S assay. Compounds 5b and 5e were determined to be full mu agonists, whereas compounds 6a and 6c were partial mu agonists. The in vivo antinociceptive activity of compound 5b was evaluated by the tail flick latency test, giving an ED50 of 2.5 mg/kg.

Inhibition of human liver microsomal (S)-nicotine oxidation by (-)-menthol and analogues.

(-)-Menthol is a widely used flavoring ingredient present in mouthwash, foods, toothpaste, and cigarettes; yet, the pharmacological effects of menthol have not been widely studied. Mentholated cigarette smoking may increase the risk for lung cancer. Many African American smokers smoke mentholated cigarettes, and African Americans have a significantly higher incidence of lung cancer as compared with whites. There may be a relationship between the incidence of lung cancer and the type of cigarette smoked because the use of mentholated cigarettes by white smokers is significantly less and the incidence of lung cancer is less. The mechanism whereby (-)-menthol could increase the health risk of smoking is not known. The results of our in vitro studies herein show that (-)-menthol and synthetic congeners inhibit the microsomal oxidation of nicotine to cotinine and the P450 2A6-mediated 7-hydroxylation of coumarin. Replacement of the alcohol oxygen atom of menthol with other heteroatoms increased the potency of P450 2A6 inhibition. Thus, the K(i) value of (-)-menthol for inhibition of microsomal nicotine oxidation was 69.7 micro M but neomenthyl thiol possesses a K(i) value of 13.8 micro M. Menthylamine inhibited nicotine oxidation with a K(i) value of 49.8 micro M, but its hydroxylamine derivative gave an IC(50) value of 2.2 micro M. A series of 16 menthol derivatives and putative metabolites were procured or chemically synthesized and tested as inhibitors of P450 2A6. While highly potent inhibition of P450 2A6 was not observed for the menthol analogues examined, it is nevertheless possible that smoking mentholated cigarettes leads to inhibition of nicotine metabolism and allows the smoker to achieve a certain elevated dose of nicotine each day. This may be another example of self-medication to obtain the desired effect of nicotine.

Cyclobutenone-Based Syntheses of Polyquinanes and Bicyclo[6.3.0]undecanes by Tandem Anionic Oxy-Cope Reactions. Total Synthesis of (+/-)-Precapnelladiene.

The addition of ethenyllithium derivatives to the carbonyl of dialkyl squarate-derived bicycloheptenones, e.g., 1a and 6a, initiates a low-temperature anion-accelerated oxy-Cope rearrangement to provide polyquinanes by a transannular aldol reaction of the intermediate bicyclo[6.3.0]undecadienone 4. Additional functionality is introduced by alkylation of the enolate 3 resulting from the oxy-Cope rearrangement. Phosphorylation or triflation of enolate 3 provides an entry into the bicyclo[6.3.0]undecane ring system. An application of this new methodology is demonstrated by the total synthesis of the sesquiterpene natural product (+/-)-precapnelladiene from diisopropyl squarate (10 steps, 12%).

Individual differences in cardiovascular reactions to stress and cigarette smoking.

The present study examined the stability of cardiovascular reactions to psychological stress and cigarette smoking, and the extent to which cardiovascular reactions to stress were predictive of cardiovascular reactions to smoking. Thirty subjects were given an initial test involving two repetitions of mental arithmetic stress and paced smoking while blood pressure and heart rate were measured. Two months later, 26 of these subjects were retested in the same paradigm. Large and stable individual differences were observed in cardiovascular reactivity to both stress and smoking. Moreover, for systolic and diastolic blood pressure, but not heart rate, reactions to stress were modestly correlated with reactions to cigarette smoking. These results are consistent with the possibility that level of reactivity to cigarette smoking may constitute a risk factor for coronary heart disease, and that one or more common variables may mediate the magnitude of blood pressure reactivity to both stress and cigarette smoking.