Abstract
Ro 63–0563 [4-amino-N-(2,6 bis-methylamino-pyridin-4-yl)-benzene sulfonamide] is a high affinity 5-hydroxytryptamine6 (HT6) receptor antagonist with more than 100-fold selectivity for the 5-HT6 receptor compared with 69 other receptors and binding sites. The present study describes the properties of [3H]Ro 63–0563, the first selective 5-HT6 receptor radioligand. Specific binding of [3H]Ro 63–0563 (nonspecific binding defined in the presence of 10 μm methiothepin) to recombinant rat and human 5-HT6 receptors was saturable, rapid, and reversible with equilibrium dissociation constants (K d) of 6.8 nmand 4.96 nm, respectively. The pharmacological profile of the rat 5-HT6 receptor labeled with [3H]Ro 63–0563 (methiothepin > d-lysergic acid diethylamide > clozapine ∼ Ro 63–0563 > lisuride > ergotamine ∼ Ro 04–6790 > 5-HT > amitriptyline ∼ metergoline ∼ mianserin ∼ ritanserin > methysergide > mesulergine) was similar to that obtained by using either [3H]d-lysergic acide diethylamide or [3H]5-HT as radioligand. In equilibrium binding studies with rat striatal membranes, [3H]Ro 63–0563 labeled a single binding site with K d andB max values of 11.7 nm and 175 fmol/mg protein, respectively. In porcine striatal membranes, [3H]Ro 63–0563 also labeled a single binding site withK d andB max values of 8.0 nm and 130 fmol/mg protein, respectively. The affinities of 14 5-HT6 receptor ligands at this binding site were similar to those found for the recombinant rat and human 5-HT6receptor, which suggested the presence of 5-HT6 receptors in porcine striatum.
Footnotes
- Received February 17, 1998.
- Accepted June 5, 1998.
-
Send reprint requests to: Dr. Andrew J. Sleight, Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland. E-mail:anelrew.john.sleight{at}roche.com
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|