[3H]doxepin interactions with histamine H1-receptors and other sites in guinea pig and rat brain homogenates.
[3H]Doxepin, a tricyclic antidepressant, binds to brain homogenates with two saturable components. The high affinity component, with a dissociation constant (KD) of 0.26 nM, is associated with histamine H1-receptors. This high affinity binding shows stereospecificity in that d-chlorpheniramine is 100 times more potent than the pharmacologically less active l-isomer. Its drug specificity and regional variation closely parallel those exhibited by [3H]mepyramine binding. The drug specificity of the low affinity component is distinct from that of histamine H1-receptors, with no stereospecificity for chlorpheniramine isomers. Furthermore, all the H1-histamine antagonists tested display micromolar potency at the low-affinity doxepin sites but nanomolar potency at the high-affinity doxepin sites associated with a physiological histamine H1-receptor. The drug specificity of the low affinity site does not correspond to that of any known neurotransmitter receptor. Tricyclic antidepressants display IC50 values of 30-600 nM for the inhibition of [3H]doxepin binding to the low-affinity component with most values in the 0.1-0.3 microM affinity range.
D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D002474:Cell-Free System; D004316:Doxepin / Q000378:metabolism*; D006168:Guinea Pigs; D007700:Kinetics; D008566:Membranes / Q000378:metabolism; D051381:Rats; D011968:Receptors, Histamine / Q000378:metabolism*; D011969:Receptors, Histamine H1 / Q000187:drug effects / Q000378:metabolism*
D011968:Receptors, Histamine; D011969:Receptors, Histamine H1; D004316:Doxepin