Chem. Pharm. Bull. 54(5) 611—622 (2006)

member of the transmembrane G-protein coupled receptors family comprising d , k and m opioid receptors. Its original homology cloning and the isolation from brain extracts of the endogenous ligand, the heptadecapeptide nociceptin (NC), gave rise to a great interest in clarifying its physiological functions. The receptor, distributed in both central and peripheral nervous systems and in non-neuronal tissues, revealed to be involved in several processes including modulation of nociception, locomotor activity, reversal of stress-induced analgesia, modulation of learning and memory, regulation of neurotransmitter and hormone release, neuronal differentiation. In the last years NOP receptor has become an important biological target for a number of potential therapeutic applications associated with pain, stress and anxiety, cognitive deficiency, eating and other disorders. At the same time, consistent advances have been attained in the design and discovery of new ligands, and many nonpeptide small molecules were developed as agonists or antagonists. Among several scaffolds, spiropiperidines showed to be an interesting and promising class of NOP ligands. They are structurally related to lofentanyl (Fig. 1), a m-selective opiate ligand having also affinity for the NOP receptor. The NOP active site was first investigated by computational studies on its complex with nociceptin and lofentanyl. Anyway spiropiperidines were useful tools for the elucidation of the mechanism of interaction of small non peptidic molecules. These studies indicated the electrostatic interaction of protonated piperidinic nitrogen with Asp130 and a hydrogen bond between the small molecule and Thr305 as determinant features for affinity. Most of the spiropiperidines have been reported to possess high agonistic activity and selectivity as Ro 64-6198 (Fig. 1) which also exhibited anxiolytic properties. The interest in this scaffold of compounds also relies in their capability of reversing their biological effect after small structural modifications. Some antagonists developed by Banyu (Fig. 1) that differ from their “isomer” Ro 64-6198 in the imidazolinone amidic sequence, can be mentioned as an example. The intriguing and often complex structure–activity relationships of spiropiperidinic NOP ligands led us to synthesize a series of new spiropiperidine-quinazolinones 3 and spiropiperidine-triazoloquinazolines 4 whose structure partly recalled some very potent agonists by Roche (Fig. 1). Our aim was to explore the influence of the following structural features on affinity and selectivity: • the presence of a fused benzene ring instead of the typical N-phenyl substituent • the inversion of the NH–CO sequence respect to the lead molecules • the different length and branching of the alkylsubstituent on the cyclohexane ring • the substitution of the amidic moiety by a fused triazole ring.