Effective and safe analgesics represent an unmet medical
need for
the treatment of acute and chronic pain. A series of N-cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines
were designed, synthesized, and assayed, leading to the discovery
of a benzylamine derivative (compound 4, SLL-039) as
a highly selective and potent κ opioid agonist (κ, K
i = 0.47 nM, κ/μ = 682, κ/δ
= 283), which was confirmed by functional assays in vitro and antinociceptive assays in vivo. The in vivo effect could be blocked by pretreatment with the
selective κ antagonist nor-BNI. Moreover, this compound did
not induce sedation, a common dose limiting effect of κ opioid
receptor agonists, at its analgesic dose compared to U50,488H. The
dissociation of sedation/antinociception found in SLL-039 was assumed
to be correlated with the occupation of its benzamide motif in a unique
subsite involving V1182.63, W124EL1, and E209EL2.
A convenient Ni(II)‐catalyzed C−C and C−N cascade coupling reaction was developed to directly access various 2,4‐disubstituted imidazoles. The reaction scope covers a variety of aryl and aliphatic substitutions, which demonstrate moderate‐to‐excellent yields. The tolerance of halogen and N‐containing heterocyclic groups demonstrates the versatility of this method for further synthetic explorations.magnified image
When two oppositely charged drops come into light contact, a liquid meniscus bridge with double-cone geometry forms between the drops. Recent experiments have demonstrated the existence of a critical cone angle above which the meniscus bridge pinches off and the drops do not coalesce. This striking behavior-which has implications for processes ranging from the coarsening of emulsions to electrospray ionization in mass spectrometry-has been studied theoretically and experimentally for inertial liquid drops. Little is known, however, about the influence of the liquid viscosity on the critical cone angle. Here, we use high-fidelity numerical simulations to gain insight into the coalescence dynamics of conical drops at intermediate Reynolds numbers. The simulations, which account for viscous, inertial, and surface tension effects, predict that the critical cone angle increases as the viscosity of the drops decreases. When approaching the inertial regime, however, the predicted critical angle quickly stabilizes at approximately 27°, as observed in experiments.
OR = 1.27; 95 %CI 1.05-1.53, P = 0.01). Subgroup analyses by ethnicity showed that the association above was still obvious in Asians, but the association was still unclear in Caucasians owing to the limited sample. In summary, this meta-analysis suggests that the FAS-1377 G/A polymorphism is associated with susceptibility to gastric cancer, especially in Asians. More studies from Caucasians are needed to provide further evidence for the possible association in Caucasians.
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