作者: Alexander Heifetz ; Yael Marantz ; Zvi Naor ; Maya Topf ; Sharon Shacham ; Ori Kalid ; Merav Fichman ; Dora Warshaviak ; Shay Bar-Haim ; Noa Avisar ; Oren M. Becker ; Silvia Noiman ; Boaz Inbal

AbstractG‐protein coupled receptors (GPCRs) are a major group of drug targets for which only one x‐ray structure is known (the nondrugable rhodopsin), limiting the application of structure‐based drug discovery to GPCRs. In this paper we present the details of PREDICT, a new algorithmic approach for modeling the 3D structure of GPCRs without relying on homology to rhodopsin. PREDICT, which focuses on the transmembrane domain of GPCRs, starts from the primary sequence of the receptor, simultaneously optimizing multiple ‘decoy’ conformations of the protein in order to find its most stable structure, culminating in a virtual receptor‐ligand complex. In this paper we present a comprehensive analysis of three PREDICT models for the dopamine D2, neurokinin NK1, and neuropeptide Y Y1 receptors. A shorter discussion of the CCR3 receptor model is also included. All models were found to be in good agreement with a large body of experimental data. The quality of the PREDICT models, at least for drug discovery purposes, was evaluated by their successful utilization in in‐silico screening. Virtual screening using all three PREDICT models yielded enrichment factors 9‐fold to 44‐fold better than random screening. Namely, the PREDICT models can be used to identify active small‐molecule ligands embedded in large compound libraries with an efficiency comparable to that obtained using crystal structures for non‐GPCR targets. Proteins 2004. © 2004 Wiley‐Liss, Inc.

1997-10-01·Bioorganic & Medicinal Chemistry Letters

Synthesis and structure-activity relationships for a series of substituted pyrrolidine NK1/NK2 receptor antagonists

作者: Correll, Melinda A. ; Kudlacz, Elizabeth M. ; Maynard, George D. ; Mandagere, Arun K. ; Logan, Deborah E. ; Webster, Mark E. ; Thompson, Thomas N. ; Liu, Xiao-Gao ; Gross, Raymond S. ; Horgan, Stephen W. ; Poole, J. Chuck ; Le, Tieu-Binh ; Hwang, Kin-Kai ; Knippenberg, Robert W. ; Geary, Julie L. ; Bratton, Larry ; Boyer, Fred ; Jones, Bryan K. ; Wenstrup, David L. ; Freund, David W. ; Burkholder, Timothy P. ; Chen, Teng-Man

The authors recently described the synthesis and characterization of MDL 105,212, a non peptide tachykinin antagonist with high affinity for NK₁ and NK₂ receptors.Here, the authors report the synthesis and structure-activity relationships for a series of analogs of MDL 105,212, I (Ar₁ = 3-ClC₆H₄, 4-FC₆H₄, 3-pyridyl, etc., Ar₂ = Ph, 3-MeOC₆H₄, 4-FC₆H₄, 3-, 4-pyridyl, R₁R₂N, = H₂N, piperidino, morpholino, 4-methylpiperidino) and II (Ar₂ = Ph, 3-, 4-pyridyl, R₁R₂N = H₂N, morpholino, 4-methylpiperidino), with regards to NK₁ and NK₂ receptor binding affinity, phys.-chem. characterization; in vitro absorption potential; in vitro metabolic stability; and efficacy in a capsaicin-challenge conscious guinea pig model after oral administration.

1996-11-01·The Journal of pharmacology and experimental therapeutics

Effect of MDL 105,212, a nonpeptide NK-1/NK-2 receptor antagonist in an allergic guinea pig model.

Article

作者: Knippenberg, R W ; Kudlacz, E M ; Logan, D E ; Burkholder, T P

MDL 105,212 has been identified as a potent, nonpeptide NK-1 and NK-2 receptor antagonist that inhibits effects of substance P and neurokinin A in vitro and in vivo (Kudlacz et al., 1996). In the present study, the compound inhibited capsaicin-induced respiratory effects after p.o. administration (5-50 mg/kg) to conscious guinea pigs; nearly complete inhibition of dyspnea and cough was observed 1 hr after 50 mg/kg p.o., and efficacy persisted for approximately 11 hr. MDL 105,212 reduced pulmonary insufflation pressure and microvascular leakage in ovalbumin-sensitized animals in response to antigen-challenge relative to vehicle-treated animals. Attenuation of early-phase allergic responses may result from MDL 105,212 inhibition of antigen-induced histamine release from sensitized guinea pig lung observed in vitro. Airway hyperresponsiveness to methacholine occurred 24 hr after antigen-challenge in ovalbuminsensitized guinea pigs; this effect was inhibited by pretreatment with MDL 105,212 (50 mg/kg p.o.) 1 hr before ovalbumin exposure without affecting increased bronchoalveolar lavage eosinophil numbers. These data suggest that sensory neuropeptides play a role in some aspects of allergic airway responses and that tachykinin receptor antagonists may be useful in treatment of atopic respiratory diseases.

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