Synthesis and analgesic properties of N-substituted trans-4a-aryldecahydroisoquinolines

Abstract

A representative series of N-substituted derivatives of the morphine-based trans-4a-aryldecahydroisoquinoline were synthesized and evaluated for opioid analgesic activities. Compounds with potent analgesic activity and high affinities for the mu and kappa opioid receptors were discovered. The effect of varying the N-substituent in the trans-4a-aryldecahydroisoquinoline paralleled, to a certain extent, previous findings with other morphine part structures. Replacement of the N-methyl with a phenethyl group significantly increased analgesic potency. The N-cyclopropylmethyl analogue was found in rodents to have mixed agonist-antagonist properties; however, its antagonist activity was far weaker than those reported for the N-(cyclopropylmethyl)morphinan and -benzomorphan derivatives. Resolution of the stereoisomers and determination of their absolute configuration by X-ray crystallography showed that the opioid receptor effects were predominantly found with the 4aR,8aR isomer, the same relative absolute configuration of morphine. Unexpectedly, the 4aR,8aR N-cyclopropylmethyl analogue (compound 30), which in rodents had mixed agonist-antagonist properties similar to those of pentazocine, was found in rhesus monkeys to behave as a full morphine-like agonist.

Essential Structure of Opioid κ Receptor Agonist Nalfurafine for Binding to κ Receptor 1: Synthesis of Decahydroisoquinoline Derivatives and Their Pharmacologies

“…To the best of our knowledge, this was the first result that such simple trans-decahydroisoquinoline derivatives without an angular aryl group exhibited κ opioid receptor affinities and selectivities. [30][31][32] The angular hydroxy group in nalfurafine significantly influenced the κ selectivity, 3,8) whereas the angular substituent (H or OH) in decahydroisoquinoline derivatives 9 and 19 had minimal influence in the κ selectivity. Despite the presence of the same amide side chain with the same configuration as that of nalfurafine, the 6β-amide isomers 9b and 19b showed worse affinities and selectivities for the κ receptor than the corresponding 6α-amide compounds 9a and 19a.…”

Opioid Properties of Some Derivatives of Pethidine Based on Tropane

“…The relative orientations of the saturated heterocyclic and aromatic ring planes in opiates (Ar plane approximately coplanar to that bisecting the piperidine ring through N and C13, and held rigid, see 15) is unfavoured in simple piperidines and tropanes whose Ar group is free to rotate about the C,-C4 (C, for tropanes; see 16) bond (Allinger & Tribble 1971; Hodgson et a1 1985). It must be admitted, however, that activities above those of morphine were reported for the decahydroisoquinoline 17 in which the same considerations of rotational freedom in respect of the Ar group apply (Zimmerman 1988). The antinociceptive action of the tropane derivative, 11, an analogue of the reversed ester of pethidine, exceeded that of pethidine itself and was about a third that of morphine in mice by the hot-plate procedure (ED50 values, mg kg-' subcutaneously: I I, 3.4; pethidine, 4.7; morphine, 1.2).…”

N-Substituted cis-4a-(3-Hydroxyphenyl)-8a-methyloctahydroisoquinolines Are Opioid Receptor Pure Antagonists

“…23 The N-methyl compound, 26 (R = CH 3 ), was reported to be an opioid agonist with twice the potency of morphine in the mouse-tail flick and writhing analgesic assays. Combining this information with the in vitro pharmacological results obtained for 6a-g in this study clearly illustrates the importance of conformation to antagonist activity and provides additional support that these compounds are interacting with opioid receptors with the 4a-(3-hydroxyphenyl) group in the equatorial conformation.…”