Diels Alder Adducts

Thebaine (59), which is present in large amounts from the species of poppy Papaver bracteaturn (292), serves as the precursor for the 6,14-ewcioetheno opiates. Although the natural levorotatory isomer of thebaine is inactive as an analgesic, it was recently reported that the (+) isomer exhibits significant antinociceptive activity (369); both isomers exhibit some affinity for opioid receptors [the (+) isomer for fi receptors and the (-) isomer for 8 receptors], but the affinities were very low (juM).

The Diels-Alder reaction of thebaine with various electrophiles yields compounds (Fig. 7.19) that have extremely high potencies, over 1000-fold higher than morphine in some cases (see Refs. 370, 371). X-ray (372) and NMR (373) analysis of 19-propylthevinol, the 3-methyl ether of etorphine (42 above), indicates that the 6,14-etheno bridge is held "inside" (endo) the tetrahydrothebaine ring system and below the plane (a) of the C7-C8 bond (see Fig. 7.19 and Ref. 283); the C ring is held in a boat conformation by the 6,14-e/wio-etheno bridge.

The C7 substituent in these compounds is in the a configuration and in many cases contains a chiral center. The stereochemistry at can have significant effect on potency of the derivatives (see Ref. 283); generally, the diastereomer with the R configuration at C19 is the more potent isomer, with the differences in potencies of the diastereomers sometimes exceeding 100-fold.

A variety of C19 alcohol derivatives have been prepared (see Refs. 370,3711, and three of these compounds are frequently used in opioid research. Etorphine (42) is a potent anal

(59) Thebaine endoetheno derivatives

(59) Thebaine

R = CH3 (43) Diprenorphine R = C(CH3)3 (85) Buprenorphine ur*

R = CH3 (43) Diprenorphine R = C(CH3)3 (85) Buprenorphine endoetheno derivatives ur*

(86) BU48

Figure 7.19. Diels-Alder reaction to give 6,14-erafoetheno derivatives tf thebaine (59) and the structures of bu-prenorphine (85) and BU48 (86). The structure of diprenorphine (43) is included for comparison.

gesic, over 1000-fold more potent than morphine, which has been widely used to immobilize animals, including large game animals. It exhibits high affinity for all three opioid receptor types (see Table 7.8), and therefore [3H]etorphine has been used as a universal tritiated ligand for opioid receptors (see Section 3.2.3.2). The iV-cyclopropyl-methyl 6,14-ethano derivatives diprenorphine (43) and buprenorphine (85, Fig. 7.19), which differ only in the identity of one of the alkyl groups attached to C19 (see Refs. 374, 375 for structural studies of these compounds), exhibit antagonist and partial agonist activities, respectively. Diprenorphine also has high affinity for all three opioid receptor types and its tritiated form has been used as a universal tritiated ligand for opioid receptors (see Section 3.2.3.2); it antagonizes fx, 6, and k ligands in the MVD (see Table 7.8). Buprenorphine, which is used clinically, is a potent partial agonist at preceptors with antagonist (or partial agonist) activity at k receptors (376). This very lipophilic agent dissociates slowly from opioid receptors, and its complex pharmacology is not completely understood (see Ref. 307). Its unique pharmacological profile offers several clinical advantages; it causes less severe respiratory depression than full agonists and has less abuse potential. It can suppress withdrawal symptoms in addicted individuals undergoing withdrawal from opiates and thus has been used in the maintenance of these patients. Because of its partial agonist activity, however, it can also precipiate withdrawal symptoms in those addicted to opiates. The 18,19-dehydro derivative of buprenorphine HS-599 exhibits higher affinity, selectivity, and potency at iu, receptors than does the parent compound (377). A series of buprenorphine analogs were prepared in which C20 was constrained in a five-membered ring to assess the influence of the orientation of the C20 hy-on activity; although the configuration of this hydroxyl did not affect the binding affinity, it did influence K-receptor efficacy and potency (378). One of these novel ring-constrained analogs BU48 (86) exhibits an unusual pattern of pharmacological activity, producing 6 opioid receptor-mediated convulsions but not 8 receptor-mediated antinociception (238).

R = CH3 (87) Levorphanol R = H (89) Dextrorphan R = CPM (88) Cyclorphan R = CH3 (90) Dextromethorphan

(91) Butorphanol

Figure 7.20. Morphinan derivatives.

(91) Butorphanol

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