Abstract
Neuropeptide S modulates important neurobiological functions including locomotion, anxiety, and drug abuse through interaction with its G protein-coupled receptor known as neuropeptide S receptor (NPSR). NPSR antagonists are potentially useful for the treatment of substance abuse disorders against which there is an urgent need for new effective therapeutic approaches. Potent NPSR antagonists in vitro have been discovered which, however, require further optimization of their in vivo pharmacological profile. This work describes a new series of NPSR antagonists of the oxazolo[3,4-a]pyrazine class. The guanidine derivative 16 exhibited nanomolar activity in vitro and 5-fold improved potency in vivo compared to SHA-68, a reference pharmacological tool in this field. Compound 16 can be considered a new tool for research studies on the translational potential of the NPSergic system. An in-depth molecular modeling investigation was also performed to gain new insights into the observed structure–activity relationships and provide an updated model of ligand/NPSR interactions.
Highlights
Neuropeptide S (NPS), identified in 2002 by a reverse pharmacology approach,[1] is the endogenous ligand of a previous orphan G protein-coupled receptor (GPCR), named neuropeptide S receptor (NPSR)
As depicted in Scheme 1, N-Fmoc-oxazolopiperazines with a general structure 26 were employed as synthetic precursors to obtain the final compounds 3−12 in analogy with the approach previously applied for the synthesis of 1 by Okamura et al.[10]
It can be speculated that NPSR antagonists may be useful for the treatment of other types of drug abuse, no preclinical data are currently available
Summary
Neuropeptide S (NPS), identified in 2002 by a reverse pharmacology approach,[1] is the endogenous ligand of a previous orphan G protein-coupled receptor (GPCR), named neuropeptide S receptor (NPSR). The in vitro pharmacology of the human and mouse NPSR showed that NPS increases both intracellular calcium levels and cAMP accumulation with EC50 values in the low nanomolar range. This indicates that NPSR can signal via both Gq and Gs pathways to increase cellular excitability.[2,3] In the rodent brain, NPS is expressed only in few neurons in the perilocus coeruleus region. NPSR antagonists may be useful to treat substance abuse disorders against which there is an urgent need for the exploration of Received: December 22, 2020 Published: March 18, 2021
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