HISTAMINE H1‐AGONIST POTENTIATION OF ADENOSINE‐STIMULATED CYCLIC AMP ACCUMULATION IN SLICES OF GUINEA‐PIG CEREBRAL CORTEX: COMPARISON OF RESPONSE AND BINDING PARAMETERS

Abstract

1 A range of histamine analogues have been examined as potentiators of the adenosine‐stimulated accumulation of cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) in slices of guinea‐pig cerebral cortex. Dose‐response curves were constructed for the 6 most active compounds and characterized in terms of the IC₅₀, the slope and the maximum response attainable relative to that of histamine. 2 Histamine, 2‐thiazolylethylamine and N^α‐methylhistamine produced a maximal or near maximal response. N^α,N^α‐dlmethylhistamine and 2‐methylhistamine appear to be partial agonists. 3 The response to all the agonists was practically abolished by mepyramine 1 μm, indicating that the response is mediated largely or wholly via histamine H₁‐receptors. 4 The relative potencies of the agonists on cyclic AMP accumulation were in general similar to relative potencies in causing contraction of intestinal smooth muscle. The biggest difference was observed with N^α‐methylhistamine. 5 The histamine analogues were also examined as inhibitors of [³H]‐mepyramine binding in homogenates of guinea‐pig cerebral cortex. The inhibition curves were characterized in terms of IC₅₀, the slope and the maximum percentage inhibition. This last value was compared with the inhibition produced by promethazine 2 μm. 6 For the 6 most potent agonists, the EC₅₀ for cyclic AMP accumulation was compared with the IC₅₀ against [³H]‐mepyramine binding, corrected for inhibition of non‐receptor binding and for competition with [³H]‐mepyramine. With the possible exception of 2‐pyridyletfiylamine, the values did not differ by more than a factor of 3.