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911.
Large-conductance voltage and Ca2+-activated potassium channels (BKCa) play a critical role in modulating contractile tone of smooth muscle, and neuronal processes. In most mammalian tissues, activation of β-adrenergic receptors and protein kinase A (PKAc) increases BKCa channel activity, contributing to sympathetic nervous system/hormonal regulation of membrane excitability. Here we report the requirement of an association of the β2-adrenergic receptor (β2AR) with the pore forming α subunit of BKCa and an A-kinase-anchoring protein (AKAP79/150) for β2 agonist regulation. β2AR can simultaneously interact with both BKCa and L-type Ca2+ channels (Cav1.2) in vivo, which enables the assembly of a unique, highly localized signal transduction complex to mediate Ca2+- and phosphorylation-dependent modulation of BKCa current. Our findings reveal a novel function for G protein-coupled receptors as a scaffold to couple two families of ion channels into a physical and functional signaling complex to modulate β-adrenergic regulation of membrane excitability. 相似文献
912.
Guo T Adang AE Dong G Fitzpatrick D Geng P Ho KK Jibilian CH Kultgen SG Liu R McDonald E Saionz KW Valenzano KJ van Straten NC Xie D Webb ML 《Bioorganic & medicinal chemistry letters》2004,14(7):1717-1720
Potent small molecule biaryl diketopiperazine FSH receptor agonists such as 10c (EC(50)=13 nM) and 11f (EC(50)=1.2 nM) were discovered through the design, synthesis and evaluation of three biaryl diketopiperazine optimization libraries with over 300 compounds. These libraries were prepared via solid-phase parallel synthesis using a cyclization-release method. 相似文献
913.
914.
Kim TS Hague AB Lee TI Lian B Tegley CM Wang X Burgess TL Qian YX Ross S Tagari P Lin CH Mayeda C Dao J Jordan S Mohr C Cheetham J Viswanadhan V Tasker AS 《Bioorganic & medicinal chemistry letters》2004,14(1):87-90
A series of (4-piperidinylphenyl)aminoethyl amides based on dipeptide anilines were synthesized and tested against cathepsin K, cathepsin L and cathepsin B. These new non-covalent inhibitors exhibited single-digit nM inhibition of the cysteine proteases. Compounds 3 and 7 demonstrated potency in both mouse and human osteoclast resorption assays. 相似文献
915.
Sutton JC Bolton SA Davis ME Hartl KS Jacobson B Mathur A Ogletree ML Slusarchyk WA Zahler R Seiler SM Bisacchi GS 《Bioorganic & medicinal chemistry letters》2004,14(9):2233-2239
A series of nonguanidine N1-activated C4-carboxy azetidinone tryptase inhibitors was prepared by solid-phase methodology to quickly assess the SAR associated with distal functionality on the N1-activating group. From these studies, potent inhibitors with improved specificity were discovered. 相似文献
916.
Eastman B Chen C Smith ND Poon S Chung J Reyes-Manalo G Cosford ND Munoz B 《Bioorganic & medicinal chemistry letters》2004,14(22):5485-5488
The SAR of the lead compounds 2a and 2b was rapidly explored. Utilizing a parallel solution-phase Suzuki coupling approach, in tandem with strong cation exchange resin (SCX) purification afforded the desired focused library. The library was evaluated in vitro, a ninefold potency increase was achieved and the preference for ortho substitution of moderate steric bulk of the fourth, phenyl ring was identified. In addition, dimethylisoxazole, as a heterocyclic replacement for the phenylic ring of the lead compound, was also identified by this approach. 相似文献
917.
Lowe DB Magnuson S Qi N Campbell AM Cook J Hong Z Wang M Rodriguez M Achebe F Kluender H Wong WC Bullock WH Salhanick AI Witman-Jones T Bowling ME Keiper C Clairmont KB 《Bioorganic & medicinal chemistry letters》2004,14(12):3155-3159
A series of (5-(2H)-isoxazolonyl) ureas were developed as nanomolar inhibitors of hormone-sensitive lipase, an enzyme of potential importance in the treatment of diabetes. 相似文献
918.
Li Q Claiborne A Li T Hasvold L Stoll VS Muchmore S Jakob CG Gu W Cohen J Hutchins C Frost D Rosenberg SH Sham HL 《Bioorganic & medicinal chemistry letters》2004,14(21):5367-5370
As a part of our efforts to identify potent inhibitors of farnesyltransferase (FTase), modification of the structure of tipifarnib through structure-based design was undertaken by replacing the 2-quinolones with 4-quinolones and pyridones, and subsequent relocation of the D-ring to the N-methyl group on the imidazole ring. This study has yielded a novel series of potent and selective FTase inhibitors. The X-ray structure of tipifarnib (1) in complex with FTase was described. 相似文献
919.
Yao S Sgarbi PW Marby KA Rabuka D O'Hare SM Cheng ML Bairi M Hu C Hwang SB Hwang CK Ichikawa Y Sears P Sucheck SJ 《Bioorganic & medicinal chemistry letters》2004,14(14):3733-3738
Glyco-optimization (OPopS) of aminoglycosides has been performed by replacing the existing sugar moiety with a variety of sugar derivatives. Glycosylation of the 6-position of nebramine provided a library of novel 4,6-linked aminoglycosides (AMGs). Among them, compounds 8b,g,i,l, and 8u with 2"-amino, 2",3"-diamino, 2",4"-diamino, 3",4"-diamino, 3"-amino groups, respectively, showed significant antimicrobial activity against Gram-(+) and -(-) bacteria. Several were particularly potent against Pseudomonus aeruginosa with MICs in the 1-2 microg/mL range. 相似文献
920.
McAtee LC Sutton SW Rudolph DA Li X Aluisio LE Phuong VK Dvorak CA Lovenberg TW Carruthers NI Jones TK 《Bioorganic & medicinal chemistry letters》2004,14(16):4225-4229
Orexins, also termed hypocretins, consist of two neuropeptide agonists (orexin A and B) interacting with two known G-protein coupled receptors (OX(1)R and OX(2)R). In addition to other biological functions, the orexin-2 receptor is thought to be an important modulator of sleep and wakefulness. Herein we describe a series of novel, selective OX(2)R antagonists consisting of substituted 4-phenyl-[1,3]dioxanes. One such antagonist is compound 9, 1-(2,4-dibromo-phenyl)-3-((4S,5S)-2,2-dimethyl-4-phenyl-[1,3]dioxan-5-yl)-urea, which is bound by the OX(2)R with a pK(i) of 8.3, has a pK(b) of 7.9, and is 600-fold selective for the OX(2)R over the OX(1)R. 相似文献