Eugene Newton Greenblatt

A synthetic non-benzodiazepine ligand for benzodiazepine receptors: a probe for investigating neuronal substrates of anxiety.

CL 218,872 is the first non-benzodiazepine to selectively displace brain specific 3H-diazepam binding with a potency comparable to that of the benzodiazepines. Like the benzodiazepines, CL 218,872 increased punished responding in a conflict situation and protected against the convulsions induced by pentylenetetrazole. These three pharmacological properties are highly predictive of anxiolytic activity. Unlike the benzodiazepines, however, CL 218,872 was relatively inactive in tests designed to measure effects on neuronal systems which utilize GABA, glycine and serotonin as transmitters. Furthmore, CL 218,872 was relatively free of the ataxic and depressant side effects commonly associated with the benzodiazepines. Because of this high degree of selectivity, CL 218,872 may represent a new probe for investigating neuronal substrates of anxiety.

The separation of 3H-benzodiazepine binding sites in brain and of benzodiazepine pharmacological properties.

In addition to anxiolytic and anticonvulsant properties, benzodiazepines (BDZ) produce sedation, ataxia, and muscular relaxation. In general, it was difficult to separate these properties within this chemical class during the search for clinically useful anxiolytics; and when BDZs were used to characterize 3H-BDZ binding sites they indicated only a single homogenous class of receptors. A new chemical series was discovered, triazolopyridazines (TPZ, prototype CL 218,872), which showed anticonflict activity in rats and monkeys without sedation or ataxia and inhibited 3H-BDZ binding in brain membranes with kinetic characteristics suggesting the presence of multiple BDZ receptors. High affinity and low affinity sites for the TPZ were demonstrated, the former designated at Type 1 and the latter as Type 2. Anatomical and in vivo studies have supported different distributions of each receptor in brain. Lately, the physical separation of discrete proteins which bind 3H-BDZ has been reported. The multiple receptors and the variety of endogenous substances which have been proposed as modulators and ligands of the receptors might explain variability as well as selectivity in pharmacological properties in these drugs.

Some pharmacologic properties of thozalinone, a new excitant

Abstract Thozalinone has been shown to possess some pharmacologic actions similar to those of amphetamine and imipramine, but with important differences. It is less toxic than amphetamine, and its margin of safety in mice is greater. The stimulant action does not progress to tremors or convulsions as the dosage is increased. The anorexigenic activity of thozalinone is more pronounced and longer lasting than that of amphetamine. There is no evidence of the development of tolerance. The cardiovascular side effects of thozalinone are minimal, and analeptic actions are absent.