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Potency of 5-hydroxytryptamine1a agonists to inhibit adenylyl cyclase activity is a function of affinity for the "low-affinity" state of [3H]8-hydroxy-N,N-dipropylaminotetralin ([3H]8-OH-DPAT) binding

J Chamberlain, SJ Offord, BB Wolfe, LS Tyau, HL Wang and A Frazer

Neuropsychopharmacology Unit, Department of Veterans Affairs Medical Center, Philadelphia, Pennsylvania.

In this study, the radiolabeled 5-hydroxytryptamine1A agonist, [3H]8- hydroxy-N,N-dipropylamino tetralin ([3H]8-OH-DPAT), was shown to have both a high (Kd, 0.7 +/- 0.2 nM) and a low (Kd, 17 +/- 4 nM) affinity binding component in rat hippocampal homogenate preparations in the absence of guanine nucleotides. The high-affinity binding component was markedly reduced by the elimination of Mg++ from the incubation medium and the addition of both the nonhydrolyzable guanine nucleotide guanylylimidodiphosphate (Gpp(NH)p) (100 microM) and 1.0 mM EDTA to the incubation medium. Under these latter conditions, a single binding affinity component was observed with a Kd of 11 +/- 1 nM, a value in good agreement with the value for the low-affinity component measured in the absence of Gpp(NH)p. Further, the Bmax value for the single low- affinity binding component measured in the presence of Gpp(NH)p was essentially equivalent to the total of the two Bmax values found in the absence of Gpp(NH)p. A binding assay was developed using 15 nM [3H]8-OH- DPAT to determine the affinities of serotonergic drugs for the low- affinity component of [3H]8-OH-DPAT binding and these values were compared with their affinities for the high-affinity binding component as well as their potencies in a hippocampal adenylyl cyclase assay. For agonists, the Ki value for the high-affinity binding component was always less than the low-affinity Ki value, whereas the antagonist spiperone had similar values for both the high-affinity and low- affinity binding components.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 266, Issue 2, pp. 618-625, 08/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics




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P. Butkerait, Y. Zheng, H. Hallak, T. E. Graham, H. A. Miller, K. D. Burris, P. B. Molinoff, and D. R. Manning
Expression of the Human 5-Hydroxytryptamine[IMAGE] Receptor in Sf9 Cells
J. Biol. Chem., August 4, 1995; 270(31): 18691 - 18699.
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Copyright © 1993 by the American Society for Pharmacology and Experimental Therapeutics.