Stephen M. Husbands

Novel Selective Compounds for the Investigation of Imidazoline Receptorsa

ABSTRACT: Over several years our group has sought to synthesize and identify selective ligands for imidazoline (I) receptors, in particular the I2 binding site. As a consequence, [3H]2‐(2‐benzofuranyl)‐2‐imidazoline (2BFI) has proved extremely useful for binding and autoradiographic studies. More recently we have synthesized a BU series of compounds and examined these for their affinities for both I1 and I2 binding sites. BU224 (2‐(4,5‐dihydroimidaz‐2‐yl)‐quinoline) shows high affinity for I2 receptors with a Ki of 2.1 nM. BU226 (2‐(4,5‐dihydroimidaz‐2‐yl)‐isoquinoline) demonstrated slightly higher affinity (Ki 1.4 nM) for I2 receptors, but overall BU224 displayed greater selectivity for I2 over I1 receptors (832‐fold) than BU226 (380‐fold). Both compounds showed low (μM) affinity for α2‐adrenoceptors. Given BU224s ability to cross the blood brain barrier, we predict that its in vivo effects are likely to be mediated via I2 receptors. Brain dialysis revealed BU224 to dose dependently (0–20 mg/kg ip) elevate basal noradrenaline in rat frontal cortex and basal dopamine in striatum. In a rat model of opiate withdrawal, behavioral studies showed that BU224 (10 mg/kg, sc) was able to reduce acute weight loss and diarrhea, but not the number of wet dog shakes associated with the withdrawal syndrome.

Identification of ligands selective for central I2-imidazoline binding sites.

Using radioligand binding techniques, several compounds selective for mammalian brain imidazoline 2 receptors have been identified. In rabbit brain membranes, a series of 6 and/or 7 aromatic-substituted derivatives of the alpha 2-adrenoceptor antagonist idazoxan were found to show moderate affinity for I2 receptors over alpha 2-adrenoceptors, in particular 6,7-dichloroidazoxan, which was 41 fold selective in favour of I2 receptors. Modification of the benzodioxan ring of idazoxan could also result in affinity and selectivity, which was moderate (2.7 nM, 161 fold) in the case of the 1,3-benzodioxan isomer of idazoxan (2-(1,3-benzodioxanyl)-2-imidazoline), and high (1.3 nM, 2873 fold) in the case of 2-(2-benzofuranyl-2-imidazoline) (2-BFI). Analogues of 2-BFI with halogenic substitutions of the aromatic ring were also found to retain high affinity and moderate to high selectivity for I2-sites. In particular, the 7-chloro (Ki 2.8 nM, 2192 fold) and the 4,6-dibromo (Ki 6.1 nM, 361 fold) analogues of 2-BFI. These new ligands should prove invaluable for investigating the pharmacology and physiology of I2 receptors.

14β-O-cinnamoylnaltrexone and related dihydrocodeinones are mu opioid receptor partial agonists with predominant antagonist activity

14-O-Cinnamoyl esters of naltrexone (6) were synthesized and evaluated in isolated tissue assays in vitro and in vivo in mouse antinociceptive assays. Their predominant opioid receptor activity was mu receptor (MOR) antagonism, but the unsubstituted cinnamoyl derivative (6a) had partial MOR agonist activity in vitro and in vivo. When compared to the equivalent 14-cinnamoylaminomorphinones (5), the cinnamoyloxy morphinones (6) as MOR antagonists had a shorter duration of action and were less effective as pseudoirreversible antagonists. The antinociceptive activity of the cinnamoyloxycodeinones (7) was not significantly greater than that of the morphinones (6), but they exhibited no evidence of any pseudoirreversible MOR antagonism. In both respects, these profiles differed from those of the equivalent 14-cinnamoylaminocodeinones (4).

Probes for imidazoline binding sites: Synthesis and evaluation of a selective, irreversible I2 ligand

An irreversible ligand (7) has been prepared based on the selective I2 ligand 2-BFI. Compound 7 displayed high affinity and selectivity for I2-sites and has been shown to irreversibly bind to these sites in rat brain. Compound 7 should, therefore, prove an invaluable tool for the further elucidation of I2-site function.

Methylation of the enolates of thevinone and some analogues

Abstract Branching has been introduced into various thevinone analogues by utilisation of both kinetic and thermodynamic enolates. No rearrangement was observed in the systems under study.

Ring constrained analogues of the thevinones; Diels-Alder reactions of thebaines with 1-indenone and methylene cycloalkanones

Abstract Thebaine has been shown to react with various in situ generated dienophiles to yield 7,8- and 7,7-ring constrained analogues of thevinones.

Selective κ-opioid antagonists related to naltrindole. effect of side-chain spacer in the 5′-amidinoalkyl series

The study of kappa-opioid receptor function in vivo has been hampered by the limited choice of selective kappa-antagonists. Recently discovered kappa-antagonists have not yet been utilised in vivo. We here report the synthesis and in vitro evaluation of a new amidine derivative of naltrindole. It showed substantially greater kappa-selectivity in binding assays than known analogues with shorter spacer in the amidine side chain. This indicates that in nor-BNI and related selective kappa-antagonists, the second basic centre may not be ideally located.

Morphinan cyclic imines and pyrrolidines containing a constrained phenyl group: High affinity opioid agonists

Abstract A series of morphinan derivatives which are cyclic imines and pyrrolidines containing a constrained phenyl group has been synthesised and tested for their opioid receptor binding affinity. In opioid binding assays the ligands displayed very high affinity particularly for μ receptors and some showed substantial μ selectivity.

6-O-Demethylation of the thevinols with lithium aluminium hydride: Selective demethylation of a tertiary alkyl methyl ether in the presence of an aryl methyl ether

In the pursuit of ring-constrained analogues of buprenorphine, we wished to prepare 6-O-demethylated analogues of the thevinols and orvinols. Previously it had been disclosed that lithium aluminum hydride (LAH) in THF containing a chlorinated solvent could achieve this transformation. Here we report the results of our work with LAH in the non-coordinating solvent toluene. In refluxing toluene, the selective 6-O-demethylation of thevinols could be achieved with no 3-O-demethylation being observed. It appears that a C(20)−OH or C(20)−NH2 group is needed on the substrate for this hydrogenolysis to proceed.

Ring constrained analogues of the orvinols : The furanomorphides

A series of furanomorphides were synthesised as ring-constrained analogues of buprenorphine and related orvinols. Evaluation in binding and functional assays has shown that the furanomorphides have reduced efficacy at the mu opioid receptor compared to the orvinols.