Structure–activity study of N-((trans)-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652), a bitopic ligand that acts as a negative allosteric modulator of the dopamine D2 receptor

We recently demonstrated that SB269652 (1) engages one protomer of a dopamine D2 receptor (D2R) dimer in a bitopic mode to allosterically inhibit the binding of dopamine at the other protomer. Herein, we investigate structural deter- minants for allostery, focusing on modifications to three moieties within 1. We find that orthosteric “head” groups with small 7-substituents were important to maintain the limited negative cooperativity of analogues of 1, and replacement of the tetrahydroisoquinoline head group with other D2R “privileged structures” generated orthosteric antagonists. Additionally, replacement of the cyclohexylene linker with polymethylene chains conferred linker length dependency in allosteric pharma- cology. We validated the importance of the indolic NH as a hydrogen bond donor moiety for maintaining allostery. Replacement of the indole ring with azaindole conferred a 30-fold increase in affinity while maintaining negative cooperativity. Combined, these results provide novel SAR insight for bitopic ligands that act as negative allosteric modulators of the D2R

An Improved Sandwich Theory for a better Prediction of the Wrinkling Phenomenon

An advanced design of sandwich structures does not only require the knowledge of the global stress- and deformation behaviour, but also the knowledge of the local effects, such as load singularities and the loss of stability caused by the short wave wrinkling of one (bending) or both (pressure) sandwich skins. Based on the nonlinear theory for sandwich shells with seven kinematic degrees of freedom, introduced from KÜHHORN and SCHOOP [5, 6, 7] an improved theory for plane sandwich shells with eight degrees of freedom will be presented, enabling a much better representation of the sandwich core behaviour. Due to consideration of quadratic core thickness and linear core shear strain as well as longitudinal core deformation an improved prediction of the wrinkling behaviour is succeeded even for thick cores [3] and thin skins. The kinematic quantities as well as the nonlinear-differential equations and the simplified equations of first order theory resulting from them are given. Finally applying the well known classical problems of stability loaded by pressure and bending, the efficiency of this 8 DOF-theory is demonstrated. A comparison with a detailed finite element (plain strain) calculation shows the high quality of these results. The presented sandwich theory characterized by eight degrees of freedom enables the calculation of nearly all essential sandwich phenomena even for thick cores.