(DPDPE) labelled 6-sites (Ki = 1.O4pM). CI-977 also bound with negligible affinity to [3H]-(+ )3-(1-propyl-3-piperidinyl)phenol (3-PPP) labelled a-sites (Ki = 1.9jUM) and C3H]-141-[2-thienyl]cyclohexyl)piperidine (TCP) labelled PCP sites (Ki > 10pM).3 CI-977 produced a potent inhibition of the electrically-evoked contractions of the guinea-pig ileum and rabbit vas deferens with IC5o values of 0.087nm and 3.3nm, respectively. The pK5 values for the opioid antagonists naloxone (7.6) and norbinaltorphimine (10.5) supported the K nature of the CI-977-mediated effects in the smooth muscle assays. 4 CI-977 was a potent antinociceptive agent against a mechanical noxious stimulus in rats following intravenous, intramuscular, subcutaneous and oral administration. CI-977 was also effective against mechanical and chemical noxious stimuli in the mouse but ineffective against a thermal stimulus. The antinociceptive effects produced by CI-977 were completely reversed by naloxone (1 mg kg-1, s.c.). 5 At doses close to those required to produce antinociception, CI-977 also caused a naloxone-reversible diuresis and inhibition of locomotor activity. 6 The in vitro and in vivo pharmacological profile of CI-977 demonstrates that it is a potent and selective agonist at the K-opioid receptor.

PD 117302, a new nonpeptide opioid compound shown in in vitro studies to be a selective κ‐opioid agonist, has been evaluted in vivo for antinociceptive activity and other effects characteristic of κ‐receptor activation. Dose‐related long lasting antinociception was produced by PD 117302 against a mechanical noxious stimulus in rats following intravenous, subcutaneous or oral administration. PD 117302 was effective in raising the nociceptive threshold to mechanical and chemical but not to thermal noxious stimuli in the mouse. This effect was attenuated in animals pretreated with the opioid antagonist naloxone. In addition to producing antinociception, PD 117302 also caused naloxone‐reversible locomotor impairment and diuresis, effects that are typical of κ‐agonists. PD 117302 did not cause respiratory depression, inhibition of gastrointestinal motility or naloxone‐precipated withdrawal jumping in mice, effects that are associated with actions at the μ‐opioid receptor. The pharmacological profile of PD 117302 in vivo is consistent with in vitro data suggesting that PD 117302 is a selective agonist at the κ‐opioid receptor.

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We have designed a novel series of CCK-B receptor antagonists by combining key pharmacophores, an arylurea moiety of 1 and a quinazolinone ring of 3, from two known series. Our earlier studies showed that compounds with methylene linkers in our "target" produced moderate binding affinity and selectivity for CCK-B receptors, whereas its higher and lower homologues resulted in loss of affinity. Introduction of -NH- as a linker dramatically enhanced binding affinity and selectivity for CCK-B receptors, thus providing several compounds with single-digit nanomolar binding affinity and excellent selectivity. Analogous to the earlier studies of the series of quinazolinone derivatives 3, we also found 3-isopropoxyphenyl as a preferred substitution on the N-3 quinazolinone. Electron-withdrawing substitutions on the urea terminal phenyl ring enhanced the CCK-B potency. Representative compounds of this series were tested in the functional assay and showed pure antagonist profiles. Compounds 51 and 61 were orally active in the elevated rat X-maze test. These compounds were also evaluated for their pharmacokinetic profile. The absolute oral bioavailability of compound 61 was 22% in rats.