Anxiolytic-like effects of an mGluR 5 antagonist and a mGluR 2/3 agonist, and antidepressant-like effects of an mGluR 7 agonist in the chick social separation stress test, a dual-drug screening model of treatment-resistant depression.

Modulation of glutamate receptors has demonstrated anxiolytic and/or antidepressant effects in rodent stress models. The chick social-separation stress paradigm exposes socially raised aves to an isolation stressor which elicits distress vocalizations (DVocs) in an attempt to re-establish contact. The model presents a state of panic during the first 5 min followed by a state of behavioral despair during the last 60 to 90 min. Making it useful as a dual anxiolytic/antidepressant screening assay. Further research has identified the Black Australorp strain as a stress-vulnerable, treatment-resistant, and ketamine-sensitive genetic line. Utilizing this genetic line, we sought to evaluate modulation of glutamatergic receptors for potential anxiolytic and/or antidepressant effects. Separate dose-response studies were conducted for the following drugs: the AMPA PAM LY392098, the mGluR 5 antagonist MPEP, the mGluR 2/3 agonist LY404039, the mGluR 2/3 antagonist LY341495, and the mGluR 7 agonist AMN082. The norepinephrine α2 agonist clonidine and the NMDA antagonist ketamine were included as comparison for anxiolytic (anti-panic) and antidepressant effects, respectively. As in previous studies, clonidine reduced DVoc rates during the first 5 min (attenuation of panic) and ketamine elevated DVoc rates (attenuation of behavioral despair) during the last 60 min of isolation. The mGluR 2/3 agonist LY404039 and the mGluR 5 antagonist MPEP decreased DVoc rates during the first 5 min of isolation indicative of anxiolytic effects like that of clonidine while the mGluR 7 agonist AMN082 elevated DVoc rates in the later hour of isolation, representative of antidepressant effects like that of ketamine. Collectively, these findings suggest that certain glutamate targets may be clinically useful in treating panic disorder and/or treatment-resistant depression.

Nonpungent N-AVAM Capsaicin Analogues and Cancer Therapy.

Capsaicin displays robust growth-inhibitory activity in multiple human cancers. However, the feasibility of capsaicin as a clinically relevant anticancer drug is hampered by its adverse side effects. This concern has led to extensive research focused on the isolation and synthesis of second-generation nonpungent capsaicin analogues with potent antineoplastic activity. A major class of nonpungent capsaicin-like compounds belongs to the N-acyl-vanillylamide (N-AVAM) derivatives of capsaicin (hereafter referred as N-AVAM capsaicin analogues). This perspective discusses the isolation of N-AVAM capsaicin analogues from natural sources as well as their synthesis by chemical and enzymatic methods. The perspective describes the pharmacokinetic properties and anticancer activity of N-AVAM capsaicin analogues. The signaling pathways underlying the growth-inhibitory effects of N-AVAM capsaicin analogues have also been highlighted. It is hoped that the insights obtained in this perspective will facilitate the synthesis of a second generation of N-AVAM capsaicin analogues with improved stability and growth-suppressive activity in human cancer.

Structure-Based Identification of Potent Natural Product Chemotypes as Cannabinoid Receptor 1 Inverse Agonists.

Natural products are an abundant source of potential drugs, and their diversity makes them a rich and viable prospective source of bioactive cannabinoid ligands. Cannabinoid receptor 1 (CB1) antagonists are clinically established and well documented as potential therapeutics for treating obesity, obesity-related cardiometabolic disorders, pain, and drug/substance abuse, but their associated CNS-mediated adverse effects hinder the development of potential new drugs and no such drug is currently on the market. This limitation amplifies the need for new agents with reduced or no CNS-mediated side effects. We are interested in the discovery of new natural product chemotypes as CB1 antagonists, which may serve as good starting points for further optimization towards the development of CB1 therapeutics. In search of new chemotypes as CB1 antagonists, we screened the in silico purchasable natural products subset of the ZINC12 database against our reported CB1 receptor model using the structure-based virtual screening (SBVS) approach. A total of 18 out of 192 top-scoring virtual hits, selected based on structural diversity and key protein⁻ligand interactions, were purchased and subjected to in vitro screening in competitive radioligand binding assays. The in vitro screening yielded seven compounds exhibiting >50% displacement at 10 µM concentration, and further binding affinity (Ki and IC50) and functional data revealed compound 16 as a potent and selective CB1 inverse agonist (Ki = 121 nM and EC50 = 128 nM) while three other compounds-2, 12, and 18-were potent but nonselective CB1 ligands with low micromolar binding affinity (Ki). In order to explore the structure⁻activity relationship for compound 16, we further purchased compounds with >80% similarity to compound 16, screened them for CB1 and CB2 activities, and found two potent compounds with sub-micromolar activities. Most importantly, these bioactive compounds represent structurally new natural product chemotypes in the area of cannabinoid research and could be considered for further structural optimization as CB1 ligands.

Antidepressant efficacy screening of novel targets in the chick anxiety-depression model.

The chick anxiety-depression model is a hybrid simulation, which may prove useful as an early preclinical dual pharmacological screen for novel therapeutics. Separate dose-response studies were conducted with seven test compounds that have screened positive for antidepressant effects in rodent depression models and included prasterone (5.0-40.0 mg/kg), memantine (2.5-20.0 mg/kg), ketamine (1.0-10.0 mg/kg), mifepristone (50.0-400.0 mg/kg), DOV216,303 (5.0-20.0 mg/kg), CGP36742 (2.5-15.0 mg/kg), and antalarmin (1.0-30.0 mg/kg). Chicks aged 4-6 days posthatch received test compounds intramuscularly 15 min before social separation, in which distress vocalization rates were recorded. High rates of vocalization in the first phase (0-5 min) of social separation seem to model an anxiety-like state and lower rates of vocalization in the second phase (30-60 min) seem to model a depression-like state. Prasterone, memantine, ketamine, and DOV216,303 attenuated and CPG36742 enhanced the pattern of vocalizations in the first phase. Prasterone, ketamine, mifepristone, DOV216,303, and CPG36742 attenuated and memantine and antalarmin enhanced the pattern of vocalizations in the second phase. This pattern of drug effects parallels what clinical data exist, and highlights two important characteristics of this dual-screening assay. For the compounds tested, this chick model identified phase II and III clinical failures (e.g. memantine and antalarmin) and has the potential to reveal possible contraindications of compounds (i.e. CPG36742) in cases where anxiety symptoms are concomitant with a depressive episode.

Synthesis and in vitro biological evaluation of fluoro-substituted-4-phenyl-1,2,3,6-tetrahydropyridines as monoamine oxidase B substrates.

The substrate properties of three beta-fluoro-4-phenyl-1,2,3,6-tetrahydropyridines related to the proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine have been examined in an effort to evaluate the contribution of electronic parameters to the MAO-B catalyzed allylic-alpha-carbon oxidation of the tetrahydropyridinyl system. The design, synthesis, and biological evaluation of these analogues are presented and correlations to amine ionization potentials versus substrate activity are discussed.