Two related neurokinin-1 receptor antagonists have overlapping but different binding sites

Greenfeder, Scott; Cheewatrakoolpong, Boonlert; Anthes, John C.; Billah, M. Motasim; Egan, Robert W.; Brown, J. E.; Murgolo, Nicholas

doi:10.1016/s0968-0896(97)10019-0

Cited by 14 publications

(17 citation statements)

References 26 publications

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“…2g). These data are in agreement with previous studies reporting the critical nature of this interaction in binding of CP-99,994 and other early non-peptide antagonists to NK 1 R 35 . Mutation of F268 6.55 to alanine attenuates binding affinity more than 10-fold 36 , highlighting the crucial nature of the hydrophobic stacking interactions with the small-molecule core moiety on this side of the orthosteric pocket.…”

Section: Resultssupporting

confidence: 93%

“…The methoxy group points into a relatively spacious extension of this pocket comprised of residues from helices II, III and VII. Mutation of P112 3.32 to either aspartic acid or histidine results in a 4000-fold loss in binding affinity of CP-99,994 to NK 1 R 36 with mutation of F264 6.51 to alanine displaying only a moderate (4-fold) impairment of binding 35 , highlighting the importance of targeting this lipophilic local environment. However, the importance of this sub-pocket is underlined by the introduction of a more bulky tryptophan at this position leading to a >15-fold reduction in binding affinity for CP-99,994 (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Crystal structures of the human neurokinin 1 receptor in complex with clinically used antagonists

et al. 2019

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Neurokinins (or tachykinins) are peptides that modulate a wide variety of human physiology through the neurokinin G protein-coupled receptor family, implicated in a diverse array of pathological processes. Here we report high-resolution crystal structures of the human NK1 receptor (NK1R) bound to two small-molecule antagonist therapeutics – aprepitant and netupitant and the progenitor antagonist CP-99,994. The structures reveal the detailed interactions between clinically approved antagonists and NK1R, which induce a distinct receptor conformation resulting in an interhelical hydrogen-bond network that cross-links the extracellular ends of helices V and VI. Furthermore, the high-resolution details of NK1R bound to netupitant establish a structural rationale for the lack of basal activity in NK1R. Taken together, these co-structures provide a comprehensive structural basis of NK1R antagonism and will facilitate the design of new therapeutics targeting the neurokinin receptor family.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Crystal structures of the human neurokinin 1 receptor in complex with clinically used antagonists

et al. 2019

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“…[18][19][20] While secondary structure predictions have not identified H197 as Results are expressed as the Mean (7SEM) from three or more independent transfections.…”

Section: Discussionmentioning

confidence: 99%

Identification of single-nucleotide polymorphisms of the human neurokinin 1 receptor gene and pharmacological characterization of a Y192H variant

Randolph¹,

Simon²,

Arreaza³

et al. 2004

Pharmacogenomics J

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Neurokinin receptors in the central nervous system are involved in the neural circuitry of anxiety, depression and emesis. This has led to the development of nonpeptidic NK1 receptor antagonists as therapeutic agents. Clinical trials have shown that NK1 receptor antagonists have efficacy in chemotherapyinduced emesis and depression. Sequence polymorphisms can potentially influence the efficacy of drugs in patient populations and are an important consideration in the drug development process. To identify DNA sequence variants in the NK1 receptor, comparative DNA sequencing was performed on a population of 93 individuals. In total, 19 single-nucleotide polymorphisms (SNPs) were identified with one SNP (g.78351T4C) resulting in a tyrosine to histidine subsitution at residue 192 (Y192H). The Y192H variant was expressed using site-directed mutagenesis and was characterized with respect to affinity, receptor kinetics, functional calcium response and receptor internalization. In all cases the Y192H variant was found to display properties similar to those of the wild-type receptor.

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“…Preceding this profusion of small antagonist molecules, two major generations of peptidic antagonists had been proposed: peptides with d ‐amino acids, substituted with at least one d ‐Trp (8–10) and peptides with a β‐turn type II′ constraint (8–12), such as a spirolactam moiety (11). Studies with NK‐1 receptor mutants suggested that the nonpeptidic and the peptidic antagonists bind the receptor in a manner analogous to SP (13–15). In addition to these two families, Poulos et al .…”

mentioning

confidence: 99%

Analogs of Substance P modified at the C‐terminus which are both agonist and antagonist of the NK‐1 receptor depending on the second messenger pathway

Sachon¹,

Girault-Lagrange²,

Chassaing³

et al. 2002

The Journal of Peptide Research

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The initial goal of this study was to analyze, using photolabeling, the interactions between Substance P and its tachykinin NK-1 receptor. Therefore, the photoreactive amino acid para-benzoyl-phenylalanine (pBzl)Phe was incorporated into the Substance P sequence from position 4 to 11 leading to Bapa0[(pBzl)Phex]SP analogs. Biotinyl sulfone-5-aminopentanoic acid (Bapa) was introduced in order to purify the covalent complex. These photoreactive SP analogs were first assayed for their affinity for the two binding sites associated with the NK-1 receptor, as well as for their potency in activating the phospholipase C and adenylate cyclase pathways. All analogs photoreactive from position 4 to 11 have moderate to high affinity for the two NK-1 receptor-binding sites, except for the analog modified at position 7. This affinity could be correlated to their potency to activate the phospholipase C and adenylate cyclase pathways, except for the analog photoreactive at position 11. Bapa0[(pBzl)Phe11]SP was found to be an agonist in the phospholipase C pathway and an antagonist in the adenylate cyclase pathway, other analogs modified at position 11 were therefore analyzed. Among these, Bapa0[Pro9, (pBzl)Hcy(O2)11]SP is a partial agonist, whereas Bapa0[Hcy(ethylaminodansyl)11]SP is a full agonist in the phospholipase C pathway, the two analogs being antagonist in the adenylate cyclase pathway. These results show that analogs of SP can be simultaneously agonist at one binding site and antagonist at the other binding site associated with the NK-1 receptor.

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Two related neurokinin-1 receptor antagonists have overlapping but different binding sites

Cited by 14 publications

References 26 publications

Crystal structures of the human neurokinin 1 receptor in complex with clinically used antagonists

Crystal structures of the human neurokinin 1 receptor in complex with clinically used antagonists

Identification of single-nucleotide polymorphisms of the human neurokinin 1 receptor gene and pharmacological characterization of a Y192H variant

Analogs of Substance P modified at the C‐terminus which are both agonist and antagonist of the NK‐1 receptor depending on the second messenger pathway

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