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Fluoxetine, a selective inhibitor of serotonin uptake, is clinically useful in treating depression and may be useful for management of a variety of other psychiatric and metabolic derangements. Using X-ray crystallography, we have determined the three-dimensional structure of fluoxetine hydrochloride. A total of 2394 unique reflections were measured, and full-matrix least-squares refinement of all non-hydrogen coordinates and thermal parameters gave a final discrepancy index of 0.074 for 1759 observed reflections. In the solid state, the planes defined by the two aromatic rings are skewed, precluding the possibility of intramolecular ring-ring interactions. The methylene units of the methylpropanamine moiety adopt the anticipated conformational relationships to minimize torsional strain. An exact antiperiplanar relationship exists between N11 and C3; the N11-C1-C2-C3 dihedral angle is -180 degrees. The C1-C2-C3-O4 dihedral angle is 60.6 degrees, indicating that the propanamine side-chain folds toward the phenoxy moiety rather than adopting a fully extended conformation. This folded three-dimensional relationship may be necessary for high-affinity interaction with the serotonin-uptake carrier and confers considerable structural homology between this portion of fluoxetine and the phenylcyclohexylamine substructure of sertraline and EXP-561. However, the nature of substituents on the phenoxy portion of fluoxetine is also critical in determining potency and selectivity in this series of compounds.

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.

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Synthesis of 5-methyl-oxymorphone (3) was accomplished by oxidation of 5-methylthebaine (4) with performic acid, followed by catalytic hydrogenation and cleavage of the 3-Me0 group. X-Ray analysis confirmed that the 14-OH group has, like the one in oxymorphone (l), 8-orientation. Pharmacological studies in uiuo and in vitro showed 3 to possess slightly less opioid agonistic properties than 1.In our pursuit of structure-activity relationships in the N-methylmorphinan-6-one series, we have found that 14-0-methylation of oxymorphone ( = 4,5a -epoxy-3,14-dihydroxy-17-methylmorphinan-6-one; 1) results in a compound (2) which possesses much higher antinociceptive potency and opioid receptor binding affinity than the parent compound of the series, oxymorphone (1). It was of interest to determine if a 5-Me group on 1 would enhance the opioid agonistic properties to a similar extent as the 14-0-Me group. In addition, the up to now unknown structure of 5-methyl-oxymorphone (3) would be a starting point for further synthetic and pharmacologic investigations in the class of 14-hydroxy-morphinan-6-ones.Chemistry. -The oxidation of 5-methylthebaine (4) [2] [3] with rn-chloroperbenzoic acid in AcOH/CF,COOH, carried out as described for the oxidation of thebaine (5) to 14-hydroxycodeinone (7) [4], was unsuccessful; and likewise, the oxidation with performic acid employing the conditions of a published procedure [5]. However, we found that the oxidation of 5-methylthebaine (4) with performic acid proceeded smoothly at lower temperatures and prolonged reaction time (4" and 66 h instead at 40" and 6.5 h [5])