A novel potent non-benzodiazepine anxioselective agent with reduced dependence liability: ICI 198, 256.

ICI 198,256, a member of the cinnoline series, was shown to be a potent anxiolytic agent in several species of animals. In addition, ICI 198,256 exhibited potent activity as an antagonist of both metrazole and bicuculline-induced convulsions. The salient features of ICI 198,256 are that it possesses minimal sedative liability, lower ethanol interaction and possibly lower dependence liability than benzodiazepines (e.g., diazepam). Neurochemically, this structurally novel anxiolytic compound is potent and selective for the Type 1 (cerebellar) BZ receptors in vivo as well as ex vivo, and in addition shows an agonist BZ-like profile in a variety of systems. Thus, ICI 198,256 may offer several significant advantages in the treatment of anxiety in humans than existing benzodiazepines.

Synthesis and structure-activity relationships of a series of anxioselective pyrazolopyridine ester and amide anxiolytic agents.

A series of 1-substituted 4-amino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid esters and amides were synthesized and screened for anxiolytic activity in the shock-induced suppression of drinking (SSD) test. The compounds were also tested for their ability to displace [3H]flunitrazepam (FLU) from brain benzodiazepine (BZ) binding sites. Many compounds were active in these screens and, additionally, demonstrated a selectivity for the type 1 BZ (BZ1) receptor over the type 2 BZ (BZ2) receptor as indicated by Hill coefficients significantly less than unity and by analysis of [3H]FLU binding results from different brain regions. Based on the results of structure-activity studies of these compounds, a hypothesis was proposed to explain the structural features necessary for optimal interaction with brain BZ receptors. A detailed pharmacological evaluation of one of the most potent behaviorally active compounds (27) demonstrated it to be BZ1 selective; also, in comparison to diazepam, 27 showed minimal sedative and alcohol interactive properties at therapeutically effective doses.

Mushroom chemical defense : Pungent sesquiterpenoid dialdehyde antifeedant to opossum.

A new bioassay employing a natural fungivore, the opossumDidelphis virginiana, is described. Using this bioasssay, eighteen species of fungi were tested for palatability. Five species of mushrooms, all of which taste pungent to humans, were found to be unpalatable to the opossum. From the least palatable of these,Lentinellus ursinus, the pungent principle was isolated and identified as isovelleral, a previously described fungal metabolite. The compound was shown to be a potent antifeedant to opossums. By means of difference NOE and relaxation time NMR studies, the relative configuration and solution conformation of isovelleral were deduced.