318280-95-4Relevant articles and documents
Higher-Affinity Agonists of 5-HT1AR Discovered through Tuning the Binding-Site Flexibility
Lian, Peng,Li, Linlang,Geng, Chuanrong,Zhen, Xuechu,Fu, Wei
, p. 1616 - 1627 (2015/09/01)
Discovery of high-affinity and high-selectivity agonists of 5-HT1AR has become very attractive due to their potential therapeutic effects on multiple 5-HT1AR-related psychological and neurological problems. On the basis of our previously designed lead compound FW01 (Ki = 51.9 nM, denoted as 9a in the present study), we performed large-scale molecular dynamics simulations and molecular docking operations on 5-HT1AR-9a binding. We found the flip-packing events for the headgroup of 9a, and we also found that its tail group could bind flexibly at the agonist-binding site of 5-HT1AR. By finely tuning the flip-packing phenomenon of the 9a headgroup and tuning the binding flexibility of 9a tail group, we virtually designed a series of new 9a derivatives through molecular docking operations and first-principles calculations and predicted that these newly designed 9a derivatives should be higher-affinity agonists of 5-HT1AR. The computational predictions on the new 9a derivatives have been confirmed by our wet-experimental studies as chemical synthesis, binding affinity assays, and agonistic-function assays. The consistency between our computational design and wet-experimental measurements has led to our discovery of higher-affinity agonists of 5-HT1AR, with ～50-fold increase in receptor-binding affinity and ～25-fold improvements in agonistic function. In addition, our newly designed 5-HT1AR agonists showed very high selectivity of 5-HT1AR over subtype 5-HT2AR and also over three subtypes of dopamine receptors (D1, D2, and D3). (Graph Presented).
Cardioselective aryloxy- and arylthio- hydroxypropylene-piperazinyl acetanilides which affect calcium entry
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, (2008/06/13)
Novel compounds of the general formula STR1 and the pharmaceutically acceptable esters and acid addition salts thereof, wherein: R1, R2, R3, R4 and R5 are each independently hydrogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, N-optionally substituted alkylamido, except that when R1 is methyl, R4 is not methyl; or R2 and R3 together form --OCH2 O--; R6, R7, R8, R9 and R10 are each independently hydrogen, lower acyl, aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, di-lower alkyl amino; or R6 and R7 together form --CH=CH--CH=CH--; R7 and R8 together form --OCH2 O--; R11 and R12 are each independently hydrogen or lower alkyl; and W is oxygen or sulfur. These cardioselective compounds have calcium entry blockade properties and therefore are useful in therapy in the treatment of cardiovascular diseases, including arrhythmias, variant and exercise induced angina and myocardial infarction.
