RESUMO
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.
RESUMO
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 N-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.
Assuntos
Ácidos Carboxílicos/química , Isoquinolinas/síntese química , Solventes/química , Acilação , Catálise , Reação de Cicloadição , Isoquinolinas/química , Estrutura MolecularRESUMO
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 ßarrestin2 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 ßarrestin2 recruitment. The development of novel compounds, with different downstream signaling outcomes, independent of G protein/ßarrestin2 bias, provides a more diverse pharmacological toolset for use in defining complex KOR signaling and elucidating the significance of KOR-mediated signaling.
Assuntos
Analgésicos Opioides/química , Analgésicos Opioides/farmacologia , Receptores Opioides kappa/agonistas , Animais , Arrestinas/metabolismo , Benzenoacetamidas/farmacologia , Células CHO , Cricetulus , Relação Dose-Resposta a Droga , Descoberta de Drogas , Proteínas de Ligação ao GTP/metabolismo , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Pirrolidinas/farmacologia , Receptores Opioides kappa/metabolismo , Proteínas Recombinantes/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , beta-ArrestinasRESUMO
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.
Assuntos
Benzamidas/farmacologia , Receptores Opioides kappa/antagonistas & inibidores , Relação Estrutura-Atividade , Sulfonamidas/farmacologia , Animais , Arrestinas/metabolismo , Benzamidas/química , Células CHO , Técnicas de Química Sintética , Cricetulus , Avaliação Pré-Clínica de Medicamentos/métodos , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Naltrexona/análogos & derivados , Naltrexona/química , Antagonistas de Entorpecentes/química , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides kappa/genética , Sulfonamidas/química , Tetra-Hidroisoquinolinas/química , beta-ArrestinasRESUMO
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 ßarrestin2 recruitment as well as multiple downstream signaling pathways, including ERK1/2 MAPK activation. It has been suggested that the physiological effects of KOR activation result from different signaling cascades, with analgesia being G protein-mediated and dysphoria being mediated through ßarrestin2 recruitment. Dysphoria associated with KOR activation limits the therapeutic potential in the use of KOR agonists as analgesics; therefore, it may be beneficial to develop KOR agonists that are biased toward G protein coupling and away from ßarrestin2 recruitment. Here, we describe two classes of biased KOR agonists that potently activate G protein coupling but weakly recruit ßarrestin2. These potent and functionally selective small molecule compounds may prove to be useful tools for refining the therapeutic potential of KOR-directed signaling in vivo.
Assuntos
Receptores Opioides kappa/agonistas , Animais , Arrestinas/metabolismo , Células CHO , Cricetinae , Cricetulus , Descoberta de Drogas , Proteínas de Ligação ao GTP/metabolismo , Humanos , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quinolonas/síntese química , Quinolonas/farmacologia , Receptores Opioides kappa/metabolismo , Transdução de Sinais , Triazóis/síntese química , Triazóis/farmacologia , beta-ArrestinasRESUMO
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.
Assuntos
Antidepressivos/farmacologia , Ansiedade/tratamento farmacológico , Galinhas , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Animais , Antidepressivos/uso terapêutico , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Masculino , Vocalização Animal/efeitos dos fármacosRESUMO
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 5.3â (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.