The following questions are based on a drug development program being undertaken by scientists at SynAch’s competitor, MDD Pharma. This company is trying to identify new drugs that target serotonin (5-HT) signalling. They begin by running a series of newly synthesised compounds through radioligand binding studies. Based on their initial results, they decide to carry out further testing on one of these compounds, MDD001. The initial data for MDD001 obtained from radioligand competition assays, using appropriate receptor preparations and optimised conditions, are shown below.[Fill in the blank] Comment on how the IC50 values for MDD001 compare across the receptor subtypes, and what these indicate about MDD001’s interaction with these receptor subtypes.[Fill in the blank] Experiments were undertaken to investigate the effects of MDD001 on 5-HT3 receptor-mediated cell signalling. These experiments demonstrated that intracellular calcium levels increased following 5-HT3 receptor activation, and that this increase was prevented in the presence of MDD001. Describe the steps involved, from 5-HT3 receptor activation, to this increase in intracellular calcium.[Fill in the blank] Functional studies were then undertaken and a Schild analysis was carried out to determine the pA2 for MDD001 at the 5-HT3 receptor. MDD001 was tested at increasing concentrations of 10-8M, 10-7 and 10-6M. These experiments were completed using an appropriate isolated tissue preparation and a stable receptor agonist. The Schild plot obtained is shown below. Using the Schild plot: (i) determine the apparent pA2 for MDD001 at the 5-HT3 receptor; and (ii) explain how MDD001 is MOST LIKELY interacting with the 5-HT3 receptor.[Fill in the blank] A separate Schild analysis of MDD001 measures a pA2 of 6.9 at 5-HT1b receptors. If you were using MDD001 in an experiment using a preparation containing both 5-HT1b and 5-HT3 receptors, suggest a concentration that would allow for selective targetting of 5-HT3 by MDD001. Use the pA2 you determined in part (c) to help explain your answer.[Fill in the blank] Suggest ONE possible condition that MDD001 could be used to treat. Explain the basis for why MDD001 would be useful for treating this condition, including the location(s) of the relevant receptor target.[Fill in the blank] MDD001 continues into development and is tested in clinical trials to determine its pharmacokinetic profile, which is shown below. Indicate whether MDD001 is likely to be useful for the treatment of a chronic condition. Fully explain your reasoning with reference to any relevant pharmacokinetic parameters above.[Fill in the blank] Explain what might occur if a patient were to consume grapefruit juice (a known CYP450 3A4 inhibitor) while taking MDD001. In your explanation, you should address whether there will be any impact on half-life, duration of action, time to onset and circulating plasma drug concentration. If so, describe the nature of this impact.[Fill in the blank] MDD Pharma has recently acquired funding to generate a series of tryptophan hydroxylase inhibitors for preventing serotonin (5-HT) synthesis. Pharmacological data from kinetic assays testing these compounds is shown below. MDD Pharma decided to proceed with development of non-competitive inhibitors. Describe which compound you would select for further testing and justify your selection.[Fill in the blank]多项填空题