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.
Potassium ions play diverse roles in biological processes, and abnormal K(+) levels are the hallmarks of diseases. However, the potential clinical application of the developed DNA-based K(+) sensors remains a challenge due to the presence of Pb(2+) in blood samples. In this contribution, a novel colorimetric potassium sensing assay that functions in the presence of Pb(2+) is reported. This approach is based on conformational switching of a hairpin DNA structure to a G-quadruplex. Specifically, the hairpin DNA containing G-rich aptamer T30695 is exposed to successive amounts of Na(+), Pb(2+) and K(+). These cations induce formation of the corresponding metal-stabilized G-quadruplex, which acts as DNAzyme (with hemin as a cofactor) for the catalytic oxidation of ABTS by H(2)O(2). Importantly, studies presented here show that K(+) replaces Pb(2+) from the G-quadruplex to form K(+)-stabilized G-quadruplex, which differ in the catalytic behavior. With Pb(2+)-stabilized G-quadruplex as a probe, a highly sensitive and selective colorimetric detection of K(+) is achieved in the presence of Pb(2+) and excessive Na(+) (140 mM) with the detection limit of 1.9 nM. This system represents the first known DNAzyme-based colorimetric K(+) sensor, which works in the presence of Pb(2+). Finally, the sensor is successfully applied for K(+) detection in a real human serum sample containing Pb(2+).
Cross-linking of specific lipid components by proteins mediates transmembrane signaling and material transport. In this work, we conducted coarse-grained simulation to investigate the interactions of binding units of chorela toxin (CTB) with mixed ganglioside GM1 and dipalmitoylphosphatidylcholine (DPPC) lipid bilayer membrane. We determine that the binding of CTB pentamers cross-links GM1 molecules into protein-sized nanodomains that have distinct lipid order compared with the bulk. The toxin in the nanodomain partially penetrates into the membrane. The local disordering can also transmit across the membrane via lipid coupling. Comparison simulations on CTB binding to a membrane that is composed of various lipid components demonstrate that several factors are responsible for the nanodomain formation: (a) the negatively charged headgroup of a GM1 receptor is responsible for the multivalent binding; (b) the head groups being full of hydrogen-bonding donors and receptors stabilize the GM1 cluster itself and ensure the toxin binding with high affinity; and
Undue central nervous system (CNS) side effects including
dysphoria
and sedation remain to be a challenge for the development of κ
opioid receptor (KOR) agonists as effective and safe analgesics. On
the basis of our previous work on morphinan-based KOR agonists, a
series of 7α-methyl-7β-substituted northebaine derivatives
were designed, synthesized, and biologically assayed. Among others,
compound 4a (SLL-627) has been identified
as a highly selective and potent KOR agonist both in vitro and in vivo, and its molecular basis was also examined
and discussed. Besides low liability to conditioned place aversion
(CPA) test, treatment of SLL-627 was associated with
a nonreduction in locomotor activity, compared to most of the other
arylacetamide- or morphinan-based KOR agonists which generally exhibited
apparently sedative effects. This unexpected finding provides new
insights to dissociate analgesia from sedation for future discovery
of innovative KOR agonists.
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