Charles Armon Harbert

Selective and potent analgetics derived from cannabinoids.

Abstract: 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.

Chapter 5. Recent Developments Relating Serotonin and Behavior

Publisher Summary This chapter examines the behavioral effects and sensitivity related to serotonin. The techniques for manipulating 5-HT steady state levels and receptor activity are presented. Administration of 5-HTP, which is the immediate precursor of 5-HT, leads to a nonphysiological distribution of 5-HT in brain. It happens due to the ubiquitous distribution of aromatic amino acid decarboxylase. 5-HT derived from either precursor may decrease catecholamine stores by amine displacement and Trp derivatives also inhibit tyrosine hydroxylase. Conclusions based on high 5-HT levels in selected animal strains, at certain times of day, or at certain ages are confounded by multiple genetic, circadian or ontogenetic effects that covary. The rat and cat sleep results with p -chlorophenylalanine, even considered alone would suggest that 5-HT is functionally involved in normal sleep mechanisms, but these findings are in fact only the latest in a long chain of circumstantial evidence linking 5-HT to sleep. Exogenous 5-HT given intraventricularly or in the carotid and 5-HT precursors either Trp or 5-hydroxytryptophan, given peripherally, have frequently been reported to produce electrophysiological, behavioral, and clinical evidence of sedation and sleep.

Chapter 1. Antipsychotic and Antianxiety Agents

Publisher Summary This chapter examines the development of antipsychotic and antianxiety agents. Clozapine has emerged as the focus of clinical and theoretical interest in the antipsychotic area based on its extremely low incidence of extrapyramidal side reactions. Structure–activity relationships (SAR) of the tricyclic psychotherapeutics and clinical experience with the long-acting neuroleptics have been reviewed. The SAR studies in the dibenzo[b,f]thiepin and related 6,7,6 systems have shown that substitution by chlorine in the 9-position of perathiepin results in diminished activity. Important pharmacokinetic study correlated chlorpromazine (CPZ) plasma levels with therapeutic response and found that plasma levels in the range of 150–300 ng/ml usually corresponded to clinical improvement. Concomitant administration of an antiparkinson agent (trihexyphenidyl) tended to lower plasma levels of CPZ, an effect ascribed to reduce gastric motility and decreased absorption of CPZ. A series of benzodiazepine (2, halazepam) showed evidence of efficacy against acute psychotic symptoms in an uncontrolled tria1. CI-686 was predicted to have major tranquilizer activity of short duration on the basis of quantitative pharmaco-EEG studies. Butaclamol possessed pharmacological actions resembling fluphenazine, with activity residing solely in the (+)-enantiomer.