The nociceptin/orphanin FQ (N/OFQ)/N/OFQ receptor (NOP) system
controls different biological functions including pain and cough reflex.
Mixed NOP/opioid receptor agonists elicit similar effects to strong
opioids but with reduced side effects. In this work, 31 peptides with
the general sequence [Tyr/Dmt
1
,Xaa
5
]N/OFQ(1-13)-NH
2
were synthesized and pharmacologically characterized for
their action at human recombinant NOP/opioid receptors. The best results
in terms of NOP versus mu opioid receptor potency were obtained by
substituting both Tyr
1
and Thr
5
at the N-terminal
portion of N/OFQ(1-13)-NH
2
with the noncanonical amino
acid Dmt. [Dmt
1,5
]N/OFQ(1-13)-NH
2
has been identified
as the most potent dual NOP/mu receptor peptide agonist so far described.
Experimental data have been complemented by
in silico
studies to shed light on the molecular mechanisms by which the peptide
binds the active form of the mu receptor. Finally, the compound exerted
antitussive effects in an
in vivo
model of cough.
1-cyclohexyl-x-methoxybenzene is a novel psychoactive substance (NPS), first discovered in Europe in 2012 as unknown racemic mixture of its three stereoisomers: ortho, meta and para. Each of these has structural similarities with the analgesic tramadol and the dissociative anesthetic phencyclidine. In light of these structural analogies, and based on the fact that both tramadol and phencyclidine are substances that cause toxic effects in humans, the aim of this study was to investigate the in vitro and in vivo pharmacodynamic profile of these molecules, and to compare them with those caused by tramadol and phencyclidine. In vitro studies demonstrated that tramadol, ortho, meta and para were inactive at mu, kappa and delta opioid receptors. Systemic administration of the three stereoisomers impairs sensorimotor responses, modulates spontaneous motor activity, induces modest analgesia, and alters thermoregulation and cardiorespiratory responses in the mouse in some cases, with a similar profile to that of tramadol and phencyclidine. Naloxone partially prevents only the visual sensorimotor impairments caused by three stereoisomers, without preventing other effects. The present data show that 1-cyclohexyl-x-methoxybenzene derivatives cause pharmaco-toxicological effects by activating both opioid and non-opioid mechanisms and suggest that their use could potentially lead to abuse and bodily harm.
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.
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