Differential selectivities of RU 24969 and 8-OH-DPAT for the purported 5-HT1A and 5-HT1B binding sites. Correlation between 5-HT1A affinity and hypotensive activity.
RU 24969 and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) inhibited the specific binding of [3H]5-HT (2 nM) to rat brain membranes with shallow displacement curves. The displacement data were best fitted with a model of two independent, high and low affinity binding sites. Following addition of spiperone (1 microM) as a selective ligand for the putative 5-HT1A recognition site of [3H]5-HT, the displacement curve of RU 24969 underwent a leftward shift, whereas spiperone induced a shift to the right for the displacement curve of 8-OH-DPAT. In contrast to spiperone, pindolol (1 microM) shifted the displacement curve of RU 24969 to the right. These results suggest that RU 24969 possesses preference for the purported 5-HT1B subtype of central 5-HT1 recognition site. The reported significant linear correlation between hypotensive activity following intravenous (i.v.) administration to anesthetized rats and affinity for the central 5-HT1 binding site could only be maintained by incorporation of the affinity of RU 24969 for its low and 8-OH-DPAT for its high affinity binding site. Based on the proposal that the 5-HT1A site corresponds to the high affinity site of 8-OH-DPAT and the low affinity site of RU 24969, it is hypothesized that the late depressor phase of 5-HT agonists in rats is mediated by activation of peripheral (vascular) 5-HT receptors which have similarities with the 5-HT1A subtype of central 5-HT1 recognition site.
Doods
H N
HN
Kalkman
H O
HO
De Jonge
A
A
Thoolen
M J
MJ
Wilffert
B
B
Timmermans
P B
PB
Van Zwieten
P A
PA
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000758:Anesthesia; D000818:Animals; D001665:Binding Sites; D001794:Blood Pressure / Q000187:drug effects*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D010424:Pentobarbital; D010869:Pindolol / Q000494:pharmacology; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D013134:Spiperone / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D007211:Indoles; D009281:Naphthalenes; D011985:Receptors, Serotonin; D013764:Tetrahydronaphthalenes; C025145:5-methoxy 3-(1,2,3,6-tetrahydro-4-pyridinyl)1H indole; D013134:Spiperone; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D010869:Pindolol; D010424:Pentobarbital