title: Influence of trishomocubanes on sigma receptor binding of N-(1-benzyl-piperidin-4-yl)-4-[123I]iodobenzamide in vivo in the rat brain.
abstract: Three new trishomocubane analogues based on the 4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)] dodecane-3-ol skeleton have been synthesised and assessed for their affinities at both sigma-1 and sigma-2 receptors. The effect of various N-substitution on the polycyclic moiety was examined. All synthesised compounds displayed high affinity for sigma-1 receptors (9-10 nM) and good affinity for sigma-2 receptors (230-310 nM), suggesting that substitution at the nitrogen moiety of the trishomocubane is well tolerated and represents a platform for the development of improved higher affinity sigma receptor ligands. The interaction of these functionalised trishomocubanes on the binding of the known sigma receptor radioligand, 4-[123I]IBP, was evaluated in the rat brain. Although 4-[123I]IBP had been used for imaging sigma receptors in tumours, this is the first examination of sigma receptor binding in the rat brain and therefore the potential of 4-[123I]IBP for imaging the brain was also evaluated. In vivo specificity and selectivity of 4-[123I]IBP binding was examined by studying the effects of pre-administration of sigma receptor binding drugs (+)-pentazocine and unlabelled 4-IBP. This resulted in a blockade of only 42% of 4-[123I]IBP uptake in the brain indicating high degree of non-specific binding suggesting that it may not be suitable for imaging sigma receptors in the brain. The inhibition of 4-[123I]IBP uptake using the two of the three trishomocubanes displayed a consistent blockade of 48-30% in all brain structures. This demonstrates for the first time the ability of functionalised trishomocubanes to interact with sigma receptors in vivo.
authors.affiliation: Department of Pharmacology The University of Sydney, NSW 2006 Australia.
authors.forename: Xiang
authors.initials: X
authors.lastname: Liu
authors.forename: Filomena
authors.initials: F
authors.lastname: Mattner
authors.forename: Andrew
authors.initials: A
authors.lastname: Katsifis
authors.forename: MacDonald
authors.initials: M
authors.lastname: Christie
authors.forename: Michael
authors.initials: M
authors.lastname: Kassiou
mesh_terms: D000818:Animals; D001549:Benzamides / Q000493:pharmacokinetics*; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006168:Guinea Pigs; D007457:Iodine Radioisotopes; D008297:Male; D015394:Molecular Structure; D010880:Piperidines / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000187:drug effects / Q000378:metabolism*; D000097605:Sigma-1 Receptor
chemical_list: D001549:Benzamides; D001952:Bridged-Ring Compounds; D007457:Iodine Radioisotopes; D010880:Piperidines; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C106107:sigma-2 receptor; C088152:N-(N-benzylpiperidin-4-yl)-4-iodobenzamide