Neuropeptide S receptor ligands: a patent review (2005-2016)

ABSTRACT

Introduction: Neuropeptide S (NPS) is a 20-residue peptide and endogenous ligand of the NPS receptor (NPSR). This receptor was a formerly orphan GPCR whose activation increases calcium and cyclic adenosine monophosphate levels. The NPS/NPSR system is expressed in several brain regions where it controls important biological functions including locomotor activity, arousal and sleep, anxiety, food intake, memory, pain, and drug addiction.

Areas covered: This review furnishes an updated overview of the patent literature covering NPSR ligands since 2005, when the first example of an NPSR antagonist was disclosed.

Expert opinion: Several potent NPSR antagonists are available as valuable pharmacological tools despite showing suboptimal pharmacokinetic properties in vivo. The optimization of these ligands is needed to speed up their potential clinical advancement as pharmaceuticals to treat drug addiction. In order to support the design of novel NPSR antagonists, we performed a ligand-based conformational analysis recognizing some structural requirements for NPSR antagonism. The identification of small-molecule NPSR agonists now represents an unmet challenge to be addressed. These molecules will allow investigation of the beneficial effects of selective NPSR activation in a large panel of psychiatric disorders and to foresee their therapeutic potential as anxiolytics, nootropics, and analgesics.

KEYWORDS:

• Addiction
• anxiety
• neuropeptide S
• neuropeptide S receptor antagonists
• psychiatric diseases
• sleep disorders

Article highlights

• Via selective activation of the NPSR receptor, NPS modulates several biological functions including locomotor activity, arousal and sleep, anxiety, food intake, memory, pain, and drug addiction.

• Several small-molecule chemotypes featuring NPSR antagonist activity have been identified as a result of the first medicinal chemistry efforts in this field of research. Herein we provided a three-dimensional (3D) topological model indicating structural similarities among different NPSR antagonists.

• Available preclinical evidence suggests therapeutic utility of NPSR antagonists as innovative drugs to treat drug addiction, as they demonstrated to reduce cocaine/alcohol seeking and relapse in rats.

• The scientific and patent literature pointed out how NPS produces non-sedative anxiolytic, analgesic and pro-mnemonic effects after intranasal administration in rodents.

• Important epidemiological studies demonstrated the role of the NPS/NPSR system in the control of anxiety related behaviours in humans since the single nucleotide polymorphism Asn107Ile of the receptor is associated with panic disorders, anxiety and fear sensitivity.

• The identification of small-molecule agonists of the NPSR now represents a challenge to be addressed in order to pave the way to a new non-sedative approach for the treatment of a panel of psychiatric disorders, including anxiety.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

No funding to declare.