Relapse to drug taking is a major factor contributing to the low success rate of opioid addiction treatment programmes. Recently, studies have revealed a buprenorphine/naltrexone combination had successfully increased the treatment retention rate (compared to naltrexone alone) among heroin addicts (with history of cocaine abuse) who had undergone detoxification. However, buprenorphine and naltrexone could not be administered as a single formulation due to their different bioavailability, which could create compliance issues. Therefore, in this project, we aimed to synthesise a series of ligands each having the pharmacological profile of the buprenorphine/naltrexone combination (partial agonist (ORL-1 receptors), antagonist (u- and x-opioid receptors)). Based on the group's previous work, this profile can be achieved within the orvinols series. Compound BU127, a buprenorphine analogue with phenyl substituent (C20) is very close to the desired profile. Therefore, in order to optimize BU127's profile, we designed and synthesised a series of aromatic analogues, including analogues with a small group attached to the aromatic system to increase the ORL-1 receptor efficacy, while retaining the low efficacy / antagonist activity at the u-opioid receptor and antagonist activity at x-opioid receptor. However, [35S]GTPyS screening has shown a sudden increase of x-opioid receptor efficacy with these modifications. The related compound BU10119, having a Cv-methyl, met the desired profile at all targeted receptors in the [35S]GTPyS screen. A few analogues were selected for further evaluation in functional assays in the isolated tissue preparations (rat vas deferens (for the ORL-1 and u-opioid receptors) and mouse vas deferens (for the K-opioid receptor)) to estimate their binding affinity (Ks) and potency (pA2) of the compounds relative to buprenorphine, using Schild analysis and Schild equation. Of the analogues synthesised, only compounds BU127 and BU1 0119 have met the desired profile at the targeted receptors (competitive reversible at the ORL-1 and u-opioid receptors) and having binding affinity at each receptor similar to buprenorphine (ORL-1, ~- and K-opioid receptors). Based on these results, at this point, the optimum features of buprenorphine analogues in order to achieve the targeted profiles are having a small group at Cy and a 6-membered aromatic substituent at C . 20 Without any substituent group attached to the aromatic ring.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:558874 |
| Date | January 2012 |
| Creators | Ridzwan, Irna Elina |
| Contributors | Husbands, Stephen ; Bailey, Christopher |
| Publisher | University of Bath |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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