[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 (K_D) 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 stereospecifityty 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 μM affinity range.