The synthesis and analgesic testing of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]cyclohexanol (1) are described. Prior (SAR) studies led us to conclude that the pyran ring of 9-nor-9 beta-hydroxyhexahydrocannabinol (HHC) was not necessary for the expression of biological activity in this series of cannabinoids. Analysis of models and the use of molecular mechanics calculations suggested that a simpler compound, such as 1, would possess the biological activity of HHC. Compound 1 was prepared in nine steps from [3-(benzyloxy)phenyl]acetonitrile (2). Biological testing in five models of pain shows that compound 1 and morphine are equally potent as analgesics and demonstrates that the pyran ring of HHC is not necessary for biological activity. Further simplification of 1 was pursued by the synthesis of 4-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-2-pentanol (17), but this derivative exhibits significantly reduced analgesic activity.

A series of 5-aryltetrahydro-gamma-carbolines was prepared by a novel N-arylation procedure and tested for neuroleptic activity in a rat antiamphetamine model. The systematic exploration of structural parameters leading to 8-fluoro-5-(4-fluorophenyl)-2-[4-hydroxy-4-(4-fluorophenyl)butyl]-2,3,5-tetrahydro-1H-pyrido[4,3-b]indole (CP-36,584, flutroline), a potent and long-acting neuroleptic compound, is described. These semirigid compounds provide a new, structurally distinct series with which to probe the conformational requirements for potent activity at the dopamine receptor.

Δ9‐Tetrahydrocannabinol (THC) produces a multiplicity of pharmacologic effects including analgesic, antiinflammatory, anticonvulsant, antidiarrheal, antiglaucoma, antihypertensive, and sedative effects. Efforts to elucidate the neurochemical systems mediating the THC effects have used these and related endpoints. However, animal models useful for evaluating the mechanisms by which THC produces its unique subjective effects have only recently been established. The use of drugs as discriminative stimuli provides a means for studying such mechanisms, since generalization data from this test closely correlate with subjective properties observed in clinical studies. The present study examined the ability of various drugs to mimic or block the cue produced by THC In rats. In animals trained to discriminate 3.2 mg/kg THC from vehicle, generalization occurred consistently with cannabinoids such as 11‐OH‐THC, HHC, and nabilone. Stereoselective generalization was also obtained with isomers of a potent analgesic, nantradol; potencies were consistent with results from other endpoints. In contrast, THC cueing was not produced by agents acting on adrenergic, cholinergic, serotonergic, GABAergic, or opiate systems. Similarly, a number of drugs previously reported to antagonize various nonunique effects of THC uniformly failed to block its subjective properties. These results indicate that the subjective properties of THC are mediated through as yet unidentified neurochemical systems.

Based on the hypothesis that analgetic activity is a dissociable feature of the cannabinoid molecule, we examined modifications of the side chain, the phenolic moiety, and, most significantly, structures that lack the benzopyran functionality present in THC and (—)‐9‐nor‐9β‐hydroxyhexahydrocannabinol (HHC). A new grouping, the 1‐methyl‐4‐phenylbutyloxy C‐3 side chain, elaborates a unique lipopholic region. Replacement of the phenol substituent produced several derivatives which retain analgetic activity in the codeine potency range. Introduction of a weakly basic nitrogen at C‐5 and deletion of the axial methyl group in the B ring, two structural changes forbidden by traditional cannabinoid SAR, resulted in a unique family of benzoquinolines with potent analgetic activity. The prototype of this series, levonantradol, exhibits potent and stereospecific analgetic and antiemetic activity.

Effect of electroconvulsive shook (ECS) intensity on retrograde amnesia (RA) in rats was investigated by means of the 1-trial learning technique of Pearlman, Sharp less, and Jarvik (1961). Duration and wave form of ECS and interval between acquisition and ECS were held constant. RA arose only at supramaximal ECS intensities (those eliciting tonic extensor seizures). RA scores exhibited after various supramaximal ECS intensities were essentially equivalent. At 35 ma. ECS intensity those Ss exhibiting tonic extension (unlike Ss not showing extensor seizures) also exhibited RA. Duration of tonic extension in individual Ss, however, was not related to RA. Results support the consolidation theory of memory and the view that tonic extensor seizures at different supramaximal ECS intensities reflect similar convulsant phenomena.