High-affinity binding of [3H]doxepin to histamine H1-receptors in rat brain: possible identification of a subclass of histamine H1-receptors.
The binding of the radioactively labeled tricyclic antidepressant, [3H]doxepin, to rat brain tissue was examined. Scatchard plots of specific [3H]doxepin binding indicated the presence of two distinct binding sites. The equilibrium dissociation constant (KD) of the high-affinity site was 0.020 nM with a maximal binding capacity (Bmax) of 13.7 fmol/mg protein. The corresponding values for the high-affinity site were 3.6 nM and 740 fmol/mg protein, respectively. The high-affinity site was sensitive to competition by pharmacologically relevant concentrations of histamine H1 antagonists such as pyrilamine (KD = 1.0 nM), diphenhydramine (KD = 20 nM), d-chlorpheniramine (KD = 1.7 nM), and 1-chlorpheniramine (KD = 97 nM). The Bmax for [3H]doxepin binding to the high-affinity H1-receptor, however, was approximately 10% of the Bmax obtained using [3H]pyrilamine to label the H1-receptor. Various tricyclic antidepressants were very potent inhibitors at the high-affinity [3H]doxepin site. Their potencies, however, did not correlate with their potencies previously reported for the H1-receptor. The regional distribution of [3H]doxepin high-affinity sites correlated with the known distribution of H1-receptors in the rat brain. These results suggest that [3H]doxepin is binding to a subclass of histamine H1-receptors.
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D004316:Doxepin / Q000378:metabolism*; D006632:Histamine / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008566:Membranes / Q000378:metabolism; D011738:Pyrilamine / Q000378:metabolism; D051381:Rats; D011968:Receptors, Histamine / Q000378:metabolism*; D011969:Receptors, Histamine H1 / Q000145:classification / Q000378:metabolism*
D000929:Antidepressive Agents, Tricyclic; D011968:Receptors, Histamine; D011969:Receptors, Histamine H1; D004316:Doxepin; D006632:Histamine; D011738:Pyrilamine