https://nova.newcastle.edu.au/vital/access/ /manager/Index en-au 5 https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:14134 1D- subtype compared to α_1A- and α_1B-ARs. 9 out of 12 of the tested compounds displayed affinity at the α_1A and α_1D -AR subtypes and 6 displayed affinity at all three α₁-AR subtypes, no α_1B-AR selective compounds were identified. 8 of the 9 compounds with α₁-AR affinity were antagonists and one compound displayed partial agonist characteristics. This virtual screening has successfully identified an α_1A/D-AR selective antagonist, with low µM affinity with a novel structural scaffold of a an isoquinoline fused three-ring system and good lead-like qualities ideal for further drug development.]]> Wed 11 Apr 2018 14:43:43 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:16611 0.001). Trends in receptor binding site density measurements supported this observation (P = 0.07). Glucocorticoid exposure increased β₁-adrenoceptor mRNA levels in the right ventricle of preterm hearts (P = 0.008) but did not alter expression in the left ventricle (P>0.1). Relative abundance of a1A-adrenoceptor mRNA was the same in preterm and term piglet hearts (P = >0.1) but was reduced by maternal glucocorticoid treatment (P<0.01); a2A-adrenoceptor mRNA abundance was higher in untreated and glucocorticoid exposed preterm piglet hearts than in term piglets (P<0.001). There was no difference between male and female piglets in mRNA abundance of any of the genes studied. In conclusion, there is reduced mRNA abundance of β₁-adrenoceptors in the preterm pig heart. If this lower expression of β-adrenoceptors occurs in human preterm infants, it could explain their poor cardiovascular function and their frequent failure to respond to commonly used inotropes.]]> Wed 11 Apr 2018 09:23:09 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:21263 1B adrenoceptor replacing the charged aspartate, D191, as well as a potential interaction partner, K331, with uncharged alanines to observe effects on ligand binding and receptor activation. Significant 4–6 fold reductions in affinity for the endogenous agonists, epinephrine and norepinephrine were observed for receptors with the D191A mutation in the second extracellular loop. While changes in EC₅₀ were observed, operational analysis yielded no apparent change in receptor activation. Based on these findings, we suggest that D191, in the second extracellular loop of the α_1B adrenoceptor, acts as a ‘point of first contact’ for the receptor׳s endogenous agonists. Implication of the non-conserved extracellular regions of the receptor in agonist binding makes it a potential target for the design of highly selective drugs.]]> Sat 24 Mar 2018 07:54:43 AEDT ]]>