Chen-Yu Cheng

N-Cubylmethyl substituted morphinoids as novel narcotic antagonists

N-Cubylmethylnormorphine (1) and N-cubylmethylnoroxymorphone (2) have been synthesized and found to be more potent ligands at the mu and kappa opioid receptors than morphine and oxymorphone respectively. In the guinea-pig ileum preparation, compounds 1 and 2 were characterized as opioid mu antagonists (Ke = 68 and 16 nM, respectively). Compound 2 also showed effective kappa-antagonism (Ke = 22 nM). The narcotic antagonism activity of 1 has been confirmed by in vivo assays.

N-Arylated pyrrolidin-2-ones and morpholin-3-ones as potassium channel openers

Based on the most stable conformation of ZD6169, a series of N-arylated derivatives of oxazolidindione (2), morpholin-3-one (3-5), piperidin-2-one (6), and pyrrolidin-2-one (7-13) was synthesized and evaluated for potassium channel opening activity. In the in-vitro assays, N-(4-benzoylphenyl)-piperidin-2-on (6) and N-(4-benzoylphenyl)-3,3-dimethyl-pyrrolidin-2-one (9) demonstrated potent and selective relaxant activity at the bladder detrusor muscle [IC50, bladder)=7.4 and 6.7 microM, respectively; IC50 ratio (portal vein/bladder)=41 and 51, respectively].

Blockade of the development of morphine tolerance by U-50,488, an AVP antagonist or MK-801 in the rat hippocampal slice

In this study, we investigated the effects of different drugs (a κ‐opioid receptor agonist U‐50,488, a vasopressin receptor antagonist dPTyr(Me)AVP or an N‐methyl‐D‐aspartate (NMDA) receptor antagonist MK‐801) on the development of morphine tolerance in rat hippocampal slices. Hippocampal slices (450 μm) of Sprague‐Dawley rats (250–300 g) were used. Slices were continuously superfused with artificial CSF or drugs at 1 ml min−1. Nichrome wire electrodes were placed in the Schaffer‐collateral pathway and used to deliver biphasic 0.2 ms pulses of 5–30 V (0.033 Hz). A glass microelectrode was placed in the CA1 area to record population spikes. When the slices were superfused with 10 μM morphine, the amplitude of population spikes increased 2–3 fold in 30–40 min. However, this effect of morphine decreased, i.e. tolerance developed after continuous superfusion of morphine for 2–6 h. When either U‐50,488 (200 nM) or dPTyr(Me) AVP (500 pM) or MK‐801 (500 pM) was co‐superfused with morphine (10 μM), it significantly blocked the development of morphine tolerance. Nor‐BNI (a κ‐opioid receptor antagonist, 200 nM) significantly reversed the inhibitory effect of U‐50,488 but not those of dPTyr(Me)AVP or MK‐801 on the development of morphine tolerance. These data indicate that κ‐opioid receptors, AVP receptors and NMDA receptors are all involved in the development of morphine tolerance. The suppression of κ‐opioid receptor activity after chronic morphine may occur before the activation of AVP receptors or NMDA receptors during the development of morphine tolerance.

N-Acyl-1,2,3,4a,5,10b-hexahydro-[1]benzopyrano-[3,4-b][1,4]oxazine-9-carbonitriles as bladder-selective potassium channel openers

Optically active N-acyl-5,5-dimethyl-1,2,3,4a,5,10b-hexahydro-[1]benzopyrano[3,4-b][1,4]oxazine-9-carbonitriles 2-22 were synthesized as rigid analogues of cromakalim. The (4aR, 10bR)-N-benzoyl derivative (-)-11 was identified as a bladder-selective KCO (IC50, bladder = 8.2 microM, C50, portal vein = 34.5 microM). Among the analogues of 11 with substitution on the benzoyl moiety, the 3-methyl analogue (-)-14 showed highly potent and selective activity at portal vein (IC50, bladder = 279 microM, IC50, portal vein = 0.54 microM). The 4-bromo analogue (-)-19 (IC50, bladder = 2.0 microM, IC50, portal vein = 8.1 microM) and the 4-hydroxy analogue (-)-21 (IC50, bladder = 3.8 microM, IC50, portal vein = 75 microM) showed enhanced activity at the bladder, while maintaining unprecedented bladder selectivity in vitro. The N-benzenesulfonyl analogue (-)-22, a bioisoster of (-)-11, showed similar activity at the bladder with enhanced selectivity (IC50, bladder = 11.6 microM, IC50, portal vein = 120 microM).

A New Isoquinolinone Derivative with Noble Vasorelaxation Activity

The pharmacological effects of BDPBI (7-bromo-1,4-dihydro-2-phenyl-4,4-bis(4-pyridinylmethyl)2H-isoquinolin-3-one dihydrochloride) were tested on isolated endothelium-containing or denuded aorta of the guinea pig. BDPBI with the formula C27H24BrCl2N3O was synthesized starting with 3-isochromanone. In the endothelium-containing preparations of the aortic rings, phenylephrine (PHE; 10 µmol/l) elicited contracture and acetylcholine (ACh; 10 µmol/l) or BDPBI (0.01–10 µmol/l) elicited relaxation effects on the PHE-precontracted preparations. The BDPBI-elicited effect on the PHE-precontracted aortic rings was not altered in the presence of adrenergic blockers (propranolol or yohimbine; 1 µmol/l) or pretreated preparations with aspirin, indomethacin (10 µmol/l) or L-NAME (1 mmol/l). However, the relaxation effects of BDPBI were blocked if the preparations were pretreated with diphenhydramine (10 µmol/l) or chloropheniramine maleate (10 µmol/l). In contrast to lower concentrations of atropine (1 µmol/l), higher concentrations of atropine (30 µmol/l) did block the effects of BDPBI on the PHE-precontracted aortic rings. HTMT dimaleate (0.01–10 µmol/l), a histamine H1 receptor agonist, also elicited relaxation effects on the PHE-precontracted preparation, and the effects were blocked if the preparations were pretreated with diphenhydramine or chloropheniramine maleate. On isolated denuded aorta of the guinea pig, BDPBI did not elicit relaxation effects on the PHE-precontracted aortic rings. These results demonstrated that the vasorelaxation effect of BDPBI on PHE-precontracted aortic rings is partly dependent on the activation of a histaminergic receptor from the vascular endothelium. We suggested that BDPBI would be an effective vasorelaxant for cardiovascular systems.

The role of vasopressin on the effect of U-50,488 to block the development of morphine tolerance and physical dependence

Abstract U-50,488, a selective κ-opioid receptor agonist, has been reported to inhibit the development of antinociceptive tolerance to morphine in mice, rats and guinea pigs, but the mechanism involved in this action remains unknown. Since U-50,488 has been reported to supress the plasma vasopressin level, we investigated the role of vasopressin with U-50,488 in the male Sprague Dawley rat in this study. Animals (230–270 g) were chronically treated with morphine (10 mg/kg, i.p.) twice a day for 6 days in order to induce tolerance to antinociceptive effect measured by tail-flick test. Withdrawl symptoms were precipitated by naloxone (10 mg/kg, i.p.) on day 7. U-50,488 (i.p.) or AVP (i.p. or i.c.v.) or U-50,488 and AVP was (were) coadministered with chronic morphine to investigate their effects on morphine tolerance and dependence. We found that coadministration of 8 mg/kg U-50,488 (i.p.) with morphine almost completely block morphine tolerance and partially block withdrawal symptoms. In contrast, coadministration of AVP (0.3 μg/kg, i.p., or 0.01 μg, i.c.v.) with morphine and U-50,488, the effects of U-50,488 to block morphine tolerance and dependence were reversed. In addition, treatment of AVP antagonist (dPTyr(Me)AVP, 0.5 μg/kg, i.p. or 0.5 μg, i.c.v.) has the similar effect as U-50,488 to block morphine tolerance. In summary, the effect of U-50,488 to block morphine tolerance and dependence may relate to its inhibitory effect on AVP release.

Synthesis and Structure-Opioid Activity Relationships of trans-(±)-3,4-Dichloro-N-methyl-N-[4- or 5-hydroxy-2-(1-pyrrolidiny)cyclohexyl]benzeneacetamides

To explore the effects of attaching a hydroxy function to the cyclohexane ring of κ‐selective opioid N‐[2‐(1‐pyrrolidinyl)cyclohexyl]benzeneacetamides, trans‐(±)‐3,4‐dichloro‐N‐methyl‐N‐[4‐ or 5‐hydroxy‐2‐(1‐pyrrolidiny)cyclohexyl]benzeneacetamides (1–4) and their benzoates (5–8) have been synthesized in a divergent and stereoselective manner.