In vitro and in vivo comparison of two non-peptide tachykinin NK3 receptor antagonists: Improvements in efficacy achieved through enhanced brain penetration or altered pharmacological characteristics.

  title={In vitro and in vivo comparison of two non-peptide tachykinin NK3 receptor antagonists: Improvements in efficacy achieved through enhanced brain penetration or altered pharmacological characteristics.},
  author={Lee A. Dawson and Christopher James Langmead and Adeshola Dada and Jeannette M. Watson and Zining Wu and Ra{\'u}l de la Flor and Gareth A. Jones and Jane E. Cluderay and Eric Southam and Graham S Murkitt and Mark D Hill and Declan Jones and Ceri H. Davies and Jim J. Hagan and Paul W Smith},
  journal={European journal of pharmacology},
  volume={627 1-3},
Tachykinin neurokinin 3 receptor antagonists: a patent review (2005 – 2010)
This review article discusses the latest medicinal chemistry strategies used to derive novel NK3 receptor antagonists which have been patented during the period 2005 – 2010.
Tachykinin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
Antagonists such as aprepitant and fosaprepitant were approved by FDA and EMA, in combination with other antiemetic agents, for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy.
The Neurokinins: Peptidomimetic Ligand Design and Therapeutic Applications.
A necessity for molecular tools to understand the biological role of this class endogenous peptides and their receptors prompted the scientific community to design ligands displaying either agonist and antagonist activity at the three main neurokinin receptors, called NK1, NK2 and NK3.
New quinoline NK3 receptor antagonists with CNS activity.
Progress in the development of neurokinin 3 modulators for the treatment of schizophrenia: molecule development and clinical progress.
The emerging structural biology and its use in the design of molecules with increased structural diversity and predictable receptor pharmacology are discussed and the potential therapeutic utility of NK3 receptor targeted ligands are evaluated.
The Selective Neurokinin 3 Antagonist AZD2624 Does Not Improve Symptoms or Cognition in Schizophrenia: A Proof-of-Principle Study
Results of the trial do not support a role for the NK3 antagonist AZD2624 as a therapeutic treatment for acute schizophrenia when used as monotherapy.
Kisspeptin and neurokinin B analogs use in gynecological endocrinology: where do we stand?
There is a wide spectrum of therapeutic uses of Kiss-1 and NKB agonists, including the management of infertility, treatment for PCOS, functional hypothalamic amenorrhea or postmenopausal vasomotor symptoms, as well as contraceptive issues.
Population Pharmacokinetic and Pharmacodynamic Modeling of AZD4901 and Simulation to Support Dose Selection for the Phase 2a Study
Population PK and PK/PD analyses demonstrated that AZD4901 40 mg BID is a better dosing strategy to more consistently suppress testosterone during the entire dosing interval, and Consequently, 40mg BID dosing was suggested in a phase 2a trial in females with polycystic ovary syndrome, and the trial resulted in a positive outcome as shown by significant testosterone decrease compared to placebo.
The "Cyclopropyl Fragment" is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules.
  • T. Talele
  • Chemistry, Biology
    Journal of medicinal chemistry
  • 2016
The cyclopropyl ring addresses multiple roadblocks that can occur during drug discovery such as enhancing potency, reducing off-target effects, and improving the properties of drugs containing it.


In Vitro and In Vivo Characterization of the Non-peptide NK3 Receptor Antagonist SB-223412 (Talnetant): Potential Therapeutic Utility in the Treatment of Schizophrenia
Data demonstrate that talnetant is a selective, competitive, brain-penetrant NK3 receptor antagonist with the ability to modulate mesolimbic and mesocortical dopaminergic neurotransmission and hence support its potential therapeutic utility in the treatment of schizophrenia.
Nonpeptide tachykinin receptor antagonists: I. Pharmacological and pharmacokinetic characterization of SB 223412, a novel, potent and selective neurokinin-3 receptor antagonist.
The preclinical profile of SB 223412 (high affinity, selectivity, reversibility and oral activity) suggests that it will be a useful tool compound to define the physiological and pathophysiological roles of NK-3 receptors.
Permissive role of neurokinin NK3 receptors in NK1 receptor‐mediated activation of the locus coeruleus revealed by SR 142801
It is demonstrated that stimulation of NK1 and NK3 receptors located in the LC area modulates the activity of the LC‐NE system, and that the excitatory effects ofNK1 receptor agonists require NKB/NK3 receptor activation in theLC.
Two classes of structurally different antagonists display similar species preference for the human tachykinin neurokinin3 receptor.
Results indicate that the two identified residues may be involved in adopting a receptor conformation that favors the binding of NK3 antagonists that display species preference for the human NK3 receptor.
Blockade of neurokinin3 receptors antagonizes drug‐induced population response and depolarization block of midbrain dopamine neurons in guinea pigs
The results on pharmacologically induced activation and depolarization block of dopamine neurons suggest that NK3 receptors play a key role in the midbrain DA function, presumably through activation by neurokinin B.
Tachykinin Receptors: A Radioligand Binding Perspective
Current evidence suggests that tachykinin coexistence and expression of multiple receptors may also occur with postulated NK-2 and NK-1 receptor subtypes, and the convenient working hypothesis of three endogenous ligands for three basic receptor types may be too simplistic and in need of amendment.
The mammalian tachykinin receptors.
  • C. Maggi
  • Biology, Chemistry
    General pharmacology
  • 1995
Localization of Fos‐like immunoreactivity induced by the NK3 tachykinin receptor agonist, senktide, in the guinea‐pig brain
The present results are the first demonstration that senktide induces Fos‐LI in widespread areas of the guinea‐pig brain and it is proposed that NK3 tachykinin receptors may play a more extensive role in the control of diverse brain functions, including cortical processing, learning and memory, neuroendocrine and behavioural regulation, than is currently recognized.