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

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.

Effect of l-propoxyphene on plasma levels and analgesic activity of d-propoxyphene in the rat.

Oral administration of l-propoxyphene with d-propoxyphene enhances the analgesic activity of d-propoxyphene as expressed in the rat tail heat test. The combination of d- and l-propoxyphene at a dose of 10 mg/kg each was found to have activity in the analgesic assay equivalent to that observed with d-propoxyphene at a dose of 20 mg/kg. In the same test, l-propoxyphene at a dose of 40 mg/kg had no activity. Co-administration of equal amounts of l-propoxyphene with d-propoxyphene (10 mg/kg p.o.) results in an increase in circulating plasma levels of d-propoxyphene from 9 +/- 2 to 114 +/- 39 ng/ml 15 minutes after administration. The increase in plasma levels is accompanied by a proportional increase in the brain and lung levels with no significant change in the liver levels. When d-propoxyphene (4 mug/ml) was infused in the isolated perfused rat liver, over 98% of the drug was extracted in a single pass through the liver. When l-propoxyphene was added to the perfusate (4 mug/ml), the extraction of d-propoxyphene was decreased to less than 90%. These results indicate that l-propoxyphene increases the systemic availability of d-propoxyphene by altering the amount of d-propoxyphene extracted by the liver.