Abstract
A series of peptide NK2 receptor agonists was evaluated for affinity, potency, efficacy, and selectivity at human recombinant NK2 and NK1 receptors expressed in CHO cells to identify compounds with the greatest separation between NK2 and NK1 receptor agonist activity. Binding studies were performed using displacement of [125I]-NKA binding to NK2 receptors and displacement of [3H]-Septide binding to NK1 receptors expressed in CHO cells. Functional studies examining the increase in intracellular calcium levels and cyclic AMP stimulation were performed using the same cell lines. A correlation was demonstrated between binding affinities (Ki) and potency to increase intracellular calcium (EC50) for NK2 and NK1 receptors. Ranking compounds by their relative affinity (Ki) or potency (EC50) at NK2 or NK1 receptors indicated that the most selective NK2 agonists tested were [Lys5,MeLeu9,Nle10]-NKA(4-10) (NK1/NK2 Ki ratio = 674; NK1/NK2 EC50 ratio = 105) and [Arg5,MeLeu9,Nle10]-NKA(4-10) (NK1/NK2 Ki ratio = 561; NK1/NK2 EC50 ratio = 70). The endogenous peptide, NKA, lacked selectivity with an NK1/NK2 Ki ratio = 20 and NK1/NK2 EC50 ratio = 1. Of the compounds selected for evaluation in cyclic AMP stimulation assays, [β-Ala8]-NKA(4–10) had the greatest selectivity for activation of NK2 over NK1 receptors (NK1/NK2 EC50 ratio = 244), followed by [Lys5,MeLeu9,Nle10]-NKA(4-10) (ratio = 74), and NKA exhibited marginal selectivity (ratio = 2.8).
Highlights
Agonists acting at tachykinin NK2 receptors have potential as a new class of therapeutics to stimulate bladder and rectal voiding ‘on demand’ in patients with impaired voluntary control over urination and defecation
Characterization of [125I]-neurokinin A (NKA) binding to human NK2 receptors expressed in CHO cell membranes
Akaike’s Information Corrected Criteria (AICC) analysis showed that the One-Site model provided a better goodness of fit for the individual data than the Two-Site model
Summary
Agonists acting at tachykinin NK2 receptors have potential as a new class of therapeutics to stimulate bladder and rectal voiding ‘on demand’ in patients with impaired voluntary control over urination and defecation. The ability of the endogenous peptide, neurokinin A (NKA), and other NK2 agonists, to contract bladder and colon smooth muscle preparations from various species (including human) has been amply documented [1,2,3,4,5]. Potency, efficacy and selectivity of NK2 receptor agonists not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section
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