High affinity binding of tricyclic antidepressants to histamine H1-receptors: fact and artifact.

Six tricyclic antidepressants were tested for their ability to inhibit the binding of the histamine H1-receptor antagonist [3H]pyrilamine to membrane fractions from whole rat brain. Calculated inhibition constants (Ki) for the antidepressants were in the range of 2.6 x 10(-11) to 2.3 x 10(-7) M and correlated very well with their equilibrium dissociation constants derived from biological assays of the H1-receptor. Increasing the concentration of receptors present in the binding assay resulted in an overestimation of the calculated Ki's for doxepin, amitriptyline, and nortriptyline, but not for the lower affinity compounds of the series, imipramine, protriptyline, and desipramine. These results indicate: (1) the importance of receptor concentration in determining the potency of compounds which competitively inhibit, with very high affinity, the binding of a radioactively labeled ligand; (2) the need to correlate binding data with biological data.