Selective effect on punished versus unpunished responding in a conflict test as the criterion for anxiogenic activity.

The punished drinking test has been used successfully for identifying and studying anxiolytic agents. By reducing the level of punishment (i.e.

Molecular determinants of benzodiazepine receptor affinities and anticonvulsant activities.

In vivo convulsant activities profiles and receptor binding studies together with the techniques of theoretical chemistry were used to characterize 15 compounds, from five different chemical families, known to bind to the BDZ receptor. The experimental goals of this study were to determine the affinity of these analogs for this receptor, the effect of gamma-aminobutyric acid on the affinity, and, in a self-consistent manner, the nature of the activity, agonist (anticonvulsant), antagonist, or inverse agonist (proconvulsant, convulsant), elicited by binding to this receptor. To these ends, in vivo studies were made to determine the proconvulsant, convulsant, and anticonvulsant activities and antagonism to anticonvulsant activities of the 15 analogs.

Effects of addition of a 2-methyl group to ethyl nipecotates (beta-meperidines) on receptor affinities and opiate agonist/antagonist activities.

A series of 2-methyl-3-carbethoxy-3-(m-hydroxyphenyl)piperidine opiates (13a-d) with N-substituent variations have been synthesized, and their receptor affinities and in vivo agonist and antagonist activities and energy-conformational profiles have been determined. These are racemates of the alpha-epimer at the C-2 position, with a methyl group cis to the 3-phenyl group. One of the main goals of this study was to compare the conformational and pharmacological behavior of these 2-methyl "beta-meperidine" analogues to their 2-desmethyl racemic counterparts (14a-c) previously reported in the literature.

Structure-activity studies of morphine fragments. I. 4-alkyl-4-(m-hydroxy-phenyl)-piperidines.

The 4-(m-OH-phenyl)piperidines are a flexible fragment of the morphine/benzomorphan fused-ring opioids. Analogs in this family were synthesized with varying 4-alkyl substituents increasing in bulk from H through methyl, n-propyl, to t-butyl, each with the three N-substituents methyl, allyl, and phenethyl. These twelve compounds were evaluated for analgetic agonism in mice using two different models for antinociceptive activity, acetic acid writhing and tail-flick, the latter by both subcutaneous and intracerebroventricular routes of administration.

Novel mu-selective Met-enkephalinamide analogs with antagonist activity. Synthesis, receptor binding, analgesic properties and conformational studies.

Four novel mu-selective peptide antagonists have been synthesized and examined for receptor binding, analgesic agonist and antagonist activity and energy conformational properties. These peptides were designed by analogy to results of molecular modeling of 3-phenyl piperidines which led to incorporating four modified tyrosine residues, m-Tyr, beta-methyl-m-Tyr, N-phenethyl-m-Tyr and alpha, beta-dimethyl-m-Tyr into D-Ala2-Met5-enkephalinamide. Peptides were synthesized by stepwise solution synthesis using an active ester coupling procedure.