Substituted 2-Acylaminocycloalkylthiophene-3-carboxylic Acid Arylamides as Inhibitors of the Calcium-Activated Chloride Channel Transmembrane Protein 16A (TMEM16A).

Transmembrane protein 16A (TMEM16A), also called anoctamin 1 (ANO1), is a calcium-activated chloride channel expressed widely mammalian cells, including epithelia, vascular smooth muscle tissue, electrically excitable cells, and some tumors. TMEM16A inhibitors have been proposed for treatment of disorders of epithelial fluid and mucus secretion, hypertension, asthma, and possibly cancer. Herein we report, by screening, the discovery of 2-acylaminocycloalkylthiophene-3-carboxylic acid arylamides (AACTs) as inhibitors of TMEM16A and analysis of 48 synthesized analogs (10ab-10bw) of the original AACT compound (10aa). Structure-activity studies indicated the importance of benzene substituted as 2- or 4-methyl, or 4-fluoro, and defined the significance of thiophene substituents and size of the cycloalkylthiophene core. The most potent compound (10bm), which contains an unusual bromodifluoroacetamide at the thiophene 2-position, had IC50 of ∼30 nM, ∼3.6-fold more potent than the most potent previously reported TMEM16A inhibitor 4 (Ani9), and >10-fold improved metabolic stability. Direct and reversible inhibition of TMEM16A by 10bm was demonstrated by patch-clamp analysis. AACTs may be useful as pharmacological tools to study TMEM16A function and as potential drug development candidates.

Beyond the Biology: A Systematic Investigation of Noncontent Instructor Talk in an Introductory Biology Course.

Instructors create classroom environments that have the potential to impact learning by affecting student motivation, resistance, and self-efficacy. However, despite the critical importance of the learning environment in increasing conceptual understanding, little research has investigated what instructors say and do to create learning environments in college biology classrooms. We systematically investigated the language used by instructors that does not directly relate to course content and defined the construct of Instructor Talk. Transcripts were generated from a semester-long, cotaught introductory biology course (n = 270 students). Transcripts were analyzed using a grounded theory approach to identify emergent categories of Instructor Talk. The five emergent categories from analysis of more than 600 quotes were, in order of prevalence, 1) Building the Instructor/Student Relationship, 2) Establishing Classroom Culture, 3) Explaining Pedagogical Choices, 4) Sharing Personal Experiences, and 5) Unmasking Science. Instances of Instructor Talk were present in every class session analyzed and ranged from six to 68 quotes per session. The Instructor Talk framework is a novel research variable that could yield insights into instructor effectiveness, origins of student resistance, and methods for overcoming stereotype threat. Additionally, it holds promise in professional development settings to assist instructors in reflecting on the learning environments they create.