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. The development of novel compounds, with different downstream signaling outcomes, independent of G protein/βarrestin2 bias, provides a more diverse pharmacological toolset for use in defining complex KOR signaling and elucidating the significance of KOR-mediated signaling

Antalarmin

In the mol­ecule of the title compund [systematic name: N-butyl-N-ethyl-2,5,6-trimethyl-7-(2,4,6-trimethyl­phen­yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine], C24H34N4, the pyrrolopy­rimidine 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. The N atom carrying the ethyl and n-butyl groups is flattened pyramidal

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

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. Although class performance on the objective mapped to this material on the assessment did not reach statistical significance, use of this activity has allowed fruitful discussion of misunderstood concepts and facilitated multiple changes to the lecture presentation. As pharmacy schools continue to emphasize alternative learning pedagogies, publication of previously implemented activities demonstrating their use will help others apply similar methodologies

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 (5.0-40.0mg/kg), memantine (2.5-20.0mg/kg), ketamine (1.0-10.0mg/kg), mifepristone (50.0-400.0mg/kg), DOV216,303 (5.0-20.0mg/kg), CGP36742 (2.5-15.0mg/kg), and antalarmin (1.0-30.0mg/kg). Chicks aged 4-6 days posthatch received test compounds intramuscularly 15min before social separation, in which distress vocalization rates were recorded. High rates of vocalization in the first phase (0-5min) of social separation seem to model an anxiety-like state and lower rates of vocalization in the second phase (30-60min) 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. © 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

Domino Acylation/Diels–Alder Synthesis of <i>N</i>‑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. For the latter step, a significant rate difference was observed depending on whether the amino group was substituted by a phenyl or an alkyl (usually benzyl) substituent, with the former noted by NMR to be substantially slower. The Diels–Alder step was studied by density functional theory (DFT) methods, leading to the conclusion that the degree of preorganization in the starting acylated intermediate had the largest effect on the reaction barriers. In addition, the effect of electronics on the aromatic ring in <i>N</i>-phenyl substrates was studied computationally and experimentally. Overall, this protocol proved considerably more amenable to scale up compared to earlier methods by eliminating the requirement of microwave batch chemistry for this reaction as well as significantly reducing the quantity of solvent

Domino Acylation/Diels–Alder Synthesis of <i>N</i>‑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. For the latter step, a significant rate difference was observed depending on whether the amino group was substituted by a phenyl or an alkyl (usually benzyl) substituent, with the former noted by NMR to be substantially slower. The Diels–Alder step was studied by density functional theory (DFT) methods, leading to the conclusion that the degree of preorganization in the starting acylated intermediate had the largest effect on the reaction barriers. In addition, the effect of electronics on the aromatic ring in <i>N</i>-phenyl substrates was studied computationally and experimentally. Overall, this protocol proved considerably more amenable to scale up compared to earlier methods by eliminating the requirement of microwave batch chemistry for this reaction as well as significantly reducing the quantity of solvent

A Spectroscopic and Photometric Study of 12 BM Camelopardalis

Radial velocities from 1916.95 to 1991.95 and photometry from l979.25, both published and new in this paper, are presented and analyzed. A new solution of the radial velocity curve reveals a new period of 80.90 days and an eccentricity of e = 0.05 +/- 0.02, both very different from the 80.17 days and 0.35 found by Abt et al. (1969). An alternative solution with e = 0 is given because we cannot decide firmly whether or not the small eccentricity is real. We find V sin i = 11.3 +/- 0.3 km/s from Maidanak and 10 unequal depth. 0.048 mins and 0.026 mins. The orbital ephemeris for conjunction (K gisnt behind) is JD(hel.) 2,448,111.1 (+/- 0.4 days ) + 80.898 days (+/- 0.004 days ) E, consistent with both the radial velocities and the photometry. With the ellipticity effect removed, the light curve shows residual variability which we fit with a two-spot model. During the 13 years covered by photometry there were nine different starspots, the largest one producing a light loss of 0.19 mins. Rotation periods for the nine spots ranged from 78.6 +/- 0.5 days to 83.7 +/- 0.4 days from which we concluded that the K giant does rotate synchronously but with a differential rotation coefficient of k = 0.06 +/- 0.01. Lifetimes for the nine spots ranged from 1.1 to greater than 4.2 yr and were consistent with the empirical spot lifetime laws of Hall & Henry (1994). Use of the mass function, the orbital period, the V sin i, the two different ellipticity effect amplitudes, and various logical constraints led to ranges of possible masses, radii and inclinations. The most believable solution was around i = 90 deg, R1 = 24 solar radii, M1 = 1.1 solar mass, and M2 = 0.6 solar mass. THe Rossby number for the K giant is 0.48, small enough compared to the critical value of 0.65 to explain why, though rotating \u27slowly\u27, it does have large spots

Homologous serum increases fibronectin expression and cell adhesion in airway smooth muscle cells

This study describes altered patterns of growth and upregulation of fibronectin expression of cultured canine airway smooth muscle cells grown in homologous serum, which provides a model of the vascular leakage occurring in asthma, compared to fetal bovine serum (FBS). Cells were incubated in increasing concentrations of serum (2.5–40%) for 72 hours. Both homologous serum and FBS caused cellular proliferation which reached a maximum increase at 2.5–5% serum concentration. Differences in the cellular responses to the two types of sera were noted at higher concentrations of sera. At a concentration of 40% FBS, airway smooth muscle cells increased in number by 307±16% (n=5) compared to serum-free control cells, whereas in canine serum the increase in growth was significantly smaller, 239±25% (n=7) (