Neurokinin structure

Neurokinin-1 Receptor. A homology model of the neurokinin-1 (NKi) receptor was built from the X-ray structure of rhodopsin, using the MOBILE (modeling binding sites including ligand information explicitly) approach. In this procedure, a preliminary model is generated, which is afterwards refined... 

Smith, B. J., Doran, A. C., Mclean, S., Tingley III, F. D., O Neil, C. A., Kajiji, S. M., P-glycoprotein efflux at the blood-brain barrier mediates differences in brain disposition and pharmacodynamics between two structurally related neurokinin-1 receptor antagonists, J. Pharmacol. Exp. Ther. 2001, 298, 1252-1259. 

Tachykinins are among the most abundant neuropeptides in the central nervous system. Limbic structures, which are important in the control of emotional behaviors, in particular contain tachykinins and neurokinin receptor sites in high density (Honkaniemi et al. 1992 Hurd et al. 1999 Ribeiro-da-... 

The (7 )-4,4- and the 5,4-spirolactam systems were also used to induce a (1-turn in the H-Pro-Leu-Gly-NH2 sequence (i.e., 79 and 80, Scheme 30).111031 Analysis by X-ray crystallography indicated that the structures form a type-II 3-tumJ104l Previous studies 110 with a series of neurokinin antagonists had shown that the extended conformation is favored for the (/ )-4,4-spirolactam system however, the (5)-4,4-spirolactam demonstrated a type-II l-tum conformation. 

Substance P belongs to the tachykinin family of peptides, which share the common carboxyl terminal sequence Phe-X-Gly-Leu-Met. Other members of this family are neurokinin A and neurokinin B. Substance P is an undecapeptide, while neurokinins A and B are decapeptides. They have the following structures ... 

Five topics are reviewed in this volume. Chapter 1 traces the biochemical and medical significance of Vitamin D and its derivatives from the first quarter of this century, a field which continues to promise further valuable results. In contrast, the relatively recent development of neurokinin antagonists, especially NKl-selective compounds, is surveyed in Chapter 2. These compounds have potential for the treatment of pain, migraine, emesis and asthma. A plethora of types of compound structures have recently been found to possess selective antagonism for each of the neurokinin receptors. 

Hedge VR, Dai P, Chu M, Patel M, Bryant R, Terracciano J, Das PR, Puar MS. Neurokinin receptor inhibitors fermentation, isolation, physico-chemical properties, structure and biological activity. J Antibiot 50 983-991, 1997. 

A. Chollet, Probing the structure and function of the tachykinin neurokinin-2 receptor through biosynthetic incorporation of fluorescent amino acids at specific sites,/. Biol. Chem. 1996, 271, 19991-19998. 

A large number of reported peptidomimetic compounds possess very low aqueous solubility at physiological pH owing to the high lipophilicity inherent in these structures. Phosphorylation can yield improved biological activities for such compounds. This is at least the case for the phosphorylated neurokinin-1 receptor antagonist and the HIV protease inhibitor of Fig. 36.7 described by scientists from Merck and Upjohn, respectively. Clean phosphorylation methods are now available some of them are shown in Fig. 36.8. 

Figure 12.5 Structure-based virtual screening examples for GPCRs. (a) Neurokinin-1 receptor antagonist, IC50 251 nM. (b) alA receptor antagonist, K, 1.4 nM. (c) Two chemokine receptor CCR5 agonists with EC50 values of 3.0 [xM (left) and 1.9 pM (right).

MacKenzie AR, Marchington AP, Middleton DS, Newman SD, Jones BC.Structure-activity relationships of l-alkyl-5-(3,4-dichlorophenyl)- 5-[2-[(3-substituted)-l-azeti-dinyl]ethyl]-2-piperidones. 1. Selective antagonists of the neurokinin-2 receptor. J Med Chem 2002 45 5365-5377. 

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