A decrease in cortical β-adrenoceptors (down-regulation) is associated with chronic antidepressant therapies. Prejunctional α2-adrenoceptors regulate norepinephrine via negative feedback, so α2-antagonists should increase norepinephrine and induce β-adrenoceptor down-regulation. Administering 8b (0.5 mg/kg daily for 14 days) to rats significantly reduced cortical β-adrenoceptor Bmax to 57 ± 5 fmol/mg (control 72 ± 3, p < 0.05). Based on its potency and selectivity as an α2-adrenoceptor antagonist, 8b is important for pharmacological evaluation of the α2-adrenoceptor and may have clinical use for depression. Luteinizing hormone releasing hormone (LH-RH) controls gonadotropin release; chronic LH-RH agonists suppress the pituitary-gonadal axis but have side effects. We aimed to develop orally active, nonpeptidic LH-RH antagonists and found ketoconazole showed weak but competitive binding to pituitary LH-RH receptors. Structure-activity relationship studies revealed ketoconazole (8) had micromolar affinity, with a competitive interaction (increasing [125I]leuprolide Kd without changing Bmax). Itraconazole (7) lacked affinity, while analogues 6, 9, and 10 (similar to LH-RH's N-terminal region) interacted with the receptor. Compounds 8 and 10 antagonized leuprolide-induced LH release in vitro (pA2 4.19 and 5.34). In castrated male rats, a 100 mg/kg intraduodenal dose of 8 caused a sustained 68% decrease in plasma LH over 6 hours. Hypercholesterolemia is a primary risk factor for coronary artery disease, and HMG-CoA reductase is the key regulatory enzyme in cholesterol biosynthesis. We report a novel, tissue-selective, synthetic inhibitor of HMG-CoA reductase, 1 (BMY 22089).