An Active Learning Activity to Reinforce the Design Components of the Corticosteroids.

Despite the popularity of active learning applications over the past few decades, few activities have been reported for the field of medicinal chemistry. The purpose of this study is to report a new active learning activity, describe participant contributions, and examine participant performance on the assessment questions mapped to the objective covered by the activity. In this particular activity, students are asked to design two novel corticosteroids as a group (6-8 students per group) based on the design characteristics of marketed corticosteroids covered in lecture coupled with their pharmaceutics knowledge from the previous semester and then defend their design to the class through an interactive presentation model.

Domino Acylation/Diels-Alder Synthesis of N-Alkyl-octahydroisoquinolin-1-one-8-carboxylic Acids under Low-Solvent Conditions.

The development of the domino reaction between an aminoethyl-substituted diene and maleic anhydride to afford an N-substituted octahydroisoquinolin-1-one is described. A typical procedure involves the treatment of a 1-aminoethyl-substituted butadiene with maleic anhydride at 0 °C to room temperature for 20 min under low-solvent conditions, which affords a series of isoquinolinone carboxylic acids in moderate to excellent yields. NMR monitoring suggested that the reaction proceeded via an initial acylation step followed by an intramolecular Diels-Alder reaction.

Structure-activity relationship studies of functionally selective kappa opioid receptor agonists that modulate ERK 1/2 phosphorylation while preserving G protein over βarrestin2 signaling bias.

Kappa opioid receptor (KOR) modulation is a promising target for drug discovery efforts due to KOR involvement in pain, depression, and addiction behaviors. We recently reported a new class of triazole KOR agonists that displays significant bias toward G protein signaling over βarrestin2 recruitment; interestingly, these compounds also induce less activation of ERK1/2 map kinases than the balanced agonist, U69,593. We have identified structure-activity relationships around the triazole scaffold that allows for decreasing the bias for G protein signaling over ERK1/2 activation while maintaining the bias for G protein signaling over βarrestin2 recruitment.

Potency enhancement of the κ-opioid receptor antagonist probe ML140 through sulfonamide constraint utilizing a tetrahydroisoquinoline motif.

Optimization of the sulfonamide-based kappa opioid receptor (KOR) antagonist probe molecule ML140 through constraint of the sulfonamide nitrogen within a tetrahydroisoquinoline moiety afforded a marked increase in potency. This strategy, when combined with additional structure-activity relationship exploration, has led to a compound only six-fold less potent than norBNI, a widely utilized KOR antagonist tool compound, but significantly more synthetically accessible. The new optimized probe is suitably potent for use as an in vivo tool to investigate the therapeutic potential of KOR antagonists.

Development of functionally selective, small molecule agonists at kappa opioid receptors.

The kappa opioid receptor (KOR) is widely expressed in the CNS and can serve as a means to modulate pain perception, stress responses, and affective reward states. Therefore, the KOR has become a prominent drug discovery target toward treating pain, depression, and drug addiction. Agonists at KOR can promote G protein coupling and βarrestin2 recruitment as well as multiple downstream signaling pathways, including ERK1/2 MAPK activation.

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.

Antalarmin.

In the mol-ecule of the title compund [systematic name: N-butyl-N-ethyl-2,5,6-trimethyl-7-(2,4,6-trimethyl-phen-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine], C(24)H(34)N(4), the pyrrolopy-rimidine ring system is nearly planar, its five- and six-membered rings forming a dihedral angle of 5.3 (2)°. The benzene ring is nearly orthogonal to the central ring system.