Novel kappa opioid receptor antagonists : an investigation of the duration of action and role in depression and anxiety-related behaviours

There is growing interest in kappa-opioid receptor (KOR) antagonists as potential treatments for mood disorders. Acute stress induces release of the endogenous opioid peptide dynorphin, which activates KORs. It has been postulated that KOR antagonists reduce the symptoms of depression by normalising the function of ventral tegmental area neurons, in the dopamine reward pathway, although a role for the serotoninergic dorsal raphe nucleus has also been proposed. KOR antagonists have unusually long durations of action in vivo. A single dose of the standard KOR antagonist norbinaltorphamine (norBNI) has peak effects 7-14 days post injection and inhibition lasts up to 21 days. With the aim of obtaining a short-acting KOR antagonist, in this thesis two classes of ligands were examined containing metabolically and preferentially hydrolytically sensitive groups: (i) the S'- amino- and amidino-alkyl naltrindole derivatives S'-(2-aminomethyl)naltrindole (S- AMN) and S'-(2-butylamidino)methyl naltrindole (S'-MABN) were evaluated in vivo; (ii) a novel series of trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl) piperidine (JDTic)- derivatives obtained using soft-drug design (BU090S7, BU090S8, BU090S9). Both of the naltrindole derivatives S'-AMN and S'-MABN are potent KOR antagonists in the isolated guinea-pig ileum preparation (pAz 7.43 and 8.18, respectively). However, neither compound is short-acting, with S'-AMN having antagonist activity in the tail withdrawal assay up to 28 days post-injection. Both S'- AMN and S'-MABN demonstrated anti-depressant- and anxiolytic-like effects in mice in the forced swim and elevated plus maze tests. Of the JDTic derivatives, BU090S9 was a potent and selective KOR antagonist (pA2 8.4S) while BU090S7 and BU090S8 were less potent and not KOR selective (pAz 6.98 and 6.90, respectively). Furthermore, in the tail withdrawal assay BU090S9 demonstrated significant KOR antagonist activity at 1 d but not 7d post- injection, indicating a shorter duration of action than norBNI. However, none of these compounds demonstrated anti-depressant or anxiolytic-like effects in mice. Taken together these data indicate that the insertion of a hydrolytically preferable moiety can produce shorter-acting KOR antagonists than norBNI. However, this manipulation may affect the ability of the antagonists to cross the blood-brain barrier or it may be that the long-lasting nature of norBNI action is important for the anti-depressant and anxiolytic actions of KOR antagonists.EThOS - Electronic Theses Online ServiceGBUnited Kingdo