Computer-assisted analysis of dextromethorphan and (+)-3-(-3-hydroxyphenyl)-N-(1-propyl)piperidine binding sites in rat brain. Allosteric effects of ropizine

• Published in: Life sciences (1973) Vol. 47; no. 18; p. 1625
• Main Authors: Klein, M, Musacchio, J M
• Format: Journal Article
• Language: English
• Published: Netherlands 1990
• Subjects: Allosteric Site - drug effects; Animals; Binding, Competitive; Brain - metabolism; Dextromethorphan - metabolism; Electronic Data Processing; In Vitro Techniques; Kinetics; Models, Biological; Pentazocine - pharmacology; Piperazines - metabolism; Piperazines - pharmacology; Piperidines - metabolism; Rats; Rats, Inbred Strains; Tritium
• ISSN: 0024-3205
• DOI: 10.1016/0024-3205(90)90367-Z

Computer-assisted analysis of self- and cross-displacement studies between dextromethorphan (DM) and (+)-3-(3-hydroxyphenyl)-N-(1-propyl) piperidine ((+)-3-PPP) demonstrated in the rat brain the existence of two high-affinity and one low-affinity binding site for each ligand. One high-affinity site is the common DM1/sigma 1 site, the affinity of which is allosterically increased 4 to 5-fold by 10 microM ropizine. The Kd values of the DM1/sigma 1 for DM and (+)-3-PPP are 17 and 11 nM respectively. DM binds to the second high-affinity site (R2) with a Kd of 15 nM; this site has low affinity for (+)-3-PPP. Conversely, (+)-3-PPP binds with high affinity (Kd 53 nM) to another site (R3), that has low-affinity for DM. The Bmax of the common DM1/sigma 1 site in the rat is about ten times smaller than that in the guinea pig. Thus, extreme caution should be exercised in extrapolating from one species to another. Since DM and most sigma ligands bind to more than one site, not all of which are shared, it is important not to attribute the complex pharmacological effects of these ligands to a single hypothetical receptor.