A new class of high affinity opioid and opioid receptor-like receptor (ORL1 receptor, NOP receptor) ligands has been designed by conformational restriction of piperidine-based NOP receptor ligands, resulting in a novel quinolizidine scaffold. Different modifications of the pendant functional groups on the scaffold provide differential activities at the opioid and NOP receptors. While the conformational rigidity will provide an improved understanding of the NOP and opioid receptor binding pockets, these compounds also provide a new template for the design of novel opiate and NOP ligands.Nociceptin (NC, Orphanin FQ (N/OFQ)) is the endogenous ligand for the opioid receptorlike (ORL1) receptor (now called the NOP receptor). 1,2 Although NOP/ORL1 is a member of the opioid receptor family, and is a G-protein coupled receptor, it does not bind opiates with high affinity. The NOP receptor and nociceptin have been implicated in several physiological pathways including pain, anxiety, and drug addiction. 3,4 A variety of studies have suggested that NOP agonists may be useful clinically for treatment of anxiety, 5 and antagonists may have analgesic activity. [6][7][8] In addition, various pharmacological and genetic manipulations have indicated that this receptor and N/OFQ may also be involved in morphine tolerance, 9 feeding, 10 learning and memory, 11,12 cardiovascular and renal systems, 13,14 among others. Therefore, development of highly selective and potent NOP ligands could provide new classes of drugs for several human disorders.Since nociceptin is a 17-amino acid peptide, several earlier studies have resulted in the identification of modified N/OFQ-based peptide ligands for the NOP receptor (reviewed in ref 15). Very selective peptide agonists as well as antagonists have now been identified. [16][17][18] However, despite this enhanced understanding of the structural requirements of N/OFQ-like peptides, the information is not sufficient to support rational small-molecule NOP ligand design. Furthermore, the use of peptide ligands is plagued with inherent limitations with respect to metabolic stability.Recently, several small-molecule NOP agonists and antagonists have been reported in the literature 19-25 and patents (reviewed in ref 15). Several of these ligands possess very high selectivity for the NOP receptor versus other opioid receptors. For example, Kolczewski et al. recently reported novel spiropiperidine-based pyrrolo-pyrroles, of which compound 1 (Fig. 1) was identified as a potent NOP agonist (K i =0.49 nM) with >1000-fold selectivity over the μ, δ, and κ opioid receptors. 25 It is interesting to note that all small-molecule NOP ligands disclosed thus far contain a common piperidine core and bear close structural resemblance to lofentanil and the anilidopiperidine class of opioid ligands. 26 Most of these reported ligands were discovered through high throughput screening of large libraries and the resulting hits were optimized for potency and selectivity versus other opioid receptors by modifying th...
