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Regulation of σ‐Receptors: High‐ and Low‐Affinity Agonist States, GTP Shifts, and Up‐Regulation by Rimcazole and 1,3‐Di(2‐Tolyl)guanidine
Author(s) -
Beart Philip M.,
O'Shea Rbss D.,
Manallack David T.
Publication year - 1989
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1989.tb11773.x
Subject(s) - gtp' , phencyclidine , radioligand , chemistry , agonist , binding site , stereochemistry , piperidine , guanidine , receptor , g protein , biochemistry , enzyme , nmda receptor
The regulation of the central σr‐binding site was investigated using both in vitro and in vivo manipulations in conjunction with radioligand binding. The displacement of the binding of R (+)‐[ 3 H]3‐[3‐hydroxyphenyl][ N ‐(l‐pro‐pyl)piperidine ( R (+)‐{ 3 H]3‐PPP} to cortical homogenates by a range of drugs was consistent with the site labelled being a σ‐receptor. (+)‐SKF 10,047, (‐)‐SKF 10,047, (±)‐cyclazo‐cine, phencyclidine, and dexoxadrol displaced R (+)‐[ 3 H]3‐PPP with pseudo‐Hill coefficients of less than . Further analysis employing nonlinear curve fitting techniques demonstrated that displacement data for these compounds were described better by a model whereby R (+)‐[ 3 H]3(‐PPP was displaced from two discrete sites; approximately 6[5% of the total sites were in the high‐affinity state. In the presence of 10 m M Mg 2+ and 0.3 m M GTP, displacement curves for (+)‐SKF 10,047 and (±)‐cyclazocine were shifted to the right. These findings were due to the shift of some 15% of the high‐affinity binding sites to a low‐affinity state. Saturation experiments revealed that 0.3 m M GTP acted competitively to decrease the affinity of R (+)‐[ 3 H]3‐PPP for the σ suites. The σ‐binding site was thus likely to be linked to a guanine nucleotide regulatory (G) protein. Thus σ drugs could be subdivided on the basis of their GTP sensitivity and psdudo‐Hill coefficients, and by analogy with other receptors R (+)‐3‐PPP. (+)‐SKF 10,047, and (±)‐cyclazocine, may be putative σ‐agonists. l,3‐Di(2‐tolyl)guanidine (DTG), rimcazole, and haloperidol displaced R (+)‐[ 3 H]3‐PPP with pseudo‐Hill coefficients of approximately unity and thus may be σ‐antagonists. Subchronic treatment with rimcazole was characterized by slight sedation and a concomitant up‐regulation, with a decrease in the affinity, of σr‐binding sites. The schedule of rimcazole also increased dopamine turnover in the nucleus ac‐cumbens; both the concentration of 3,4‐dihydroxyphenyl‐acetic acid (DOPAC) and the DOPAC/dopamine ratio were elevated. DTG produced similar alterations to the binding parameters of the σ‐binding site; however, changes were not observed in general behavior or accumbal dopamine turnover. (T‐Receptors are likely to be linked to a G protein and are functionally involved in the CNS.