Comparison of binding parameters of sigma 1 and sigma 2 binding sites in rat and guinea pig brain membranes: novel subtype-selective trishomocubanes.
Comparisons of binding parameters of [3H](+)-pentazocine and [3H]1,3-di-o-tolylguanidine (DTG) at sigma binding sites in guinea pig and rat brain membranes demonstrated that [3H](+)-pentazocine binds to a single high-affinity site, whereas [3H]DTG binds to two high-affinity sites in both species. The Kd values of the radioligands were similar in both types of membranes. However, the density of sigma 1 sites in guinea pig was significantly higher than that of rat. Novel trishomocubanes were tested for their affinities at sigma 1 and sigma 2 binding sites in guinea pig brain membranes using [3H](+)-pentazocine and [3H]DTG as the radioligands. N-(4-Phenylbutyl)-3-hydroxy-4- azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecane (ANSTO-14) showed the highest affinity for the sigma 1 site (Ki = 9.4 nM) and 19-fold sigma 1/sigma 2 selectivity, as a result of increasing the alkyl chain between the cubane moiety and the aromatic ring. N-(3'-Fluorophenyl)methyl- 3-hydroxy-4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11]dodeca ne (ANSTO-19), displayed the highest affinity for sigma 2 sites (Ki = 19.6 nM) and 8-fold sigma 2/sigma 1 selectivity due to a fluoro substitution in the meta position of the aromatic ring. These represent structurally novel lead compounds, especially for the development of selective sigma 2 receptor ligands.
Department of Pharmacology, University of Sydney, NSW, Australia.
V H
VH
Nguyen
M
M
Kassiou
G A
GA
Johnston
M J
MJ
Christie
D000701:Analgesics, Opioid / Q000378:metabolism*; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism*; D001665:Binding Sites; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006146:Guanidines / Q000378:metabolism*; D006168:Guinea Pigs; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D010423:Pentazocine / Q000378:metabolism*; D051381:Rats; D017480:Receptors, sigma / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000701:Analgesics, Opioid; D000927:Anticonvulsants; D001952:Bridged-Ring Compounds; D006146:Guanidines; D017480:Receptors, sigma; C050232:1,3-ditolylguanidine; D010423:Pentazocine