Mechanisms for the increase in electrically stimulated [3H]norepinephrine release from rat cortical slices by N‐(n‐propyl)‐N‐(4‐pyridinyl)‐1H‐indol‐1‐amine

Abstract

AbstractN‐(n‐propyl)‐N‐(4‐pyridinyl)‐1H‐indol‐1‐amine (HP 749) is currently in clinical trials for the treatment of Alzheimer's disease (AD). While HP 749 has many pharmacological properties, the biochemical basis for its efficacy in animal models for AD remains unexplained. To this end, we have investigated some biochemical properties of HP 749 as they relate to its effect on electrically stimulated [3H]norepinephrine (NE) release. HP 749 was found to inhibit both [3H]NE uptake and [3H]yohimbine binding to cortical μ2‐adrenergic receptors. Consistent with this profile, HP 749 (1 and 10 μM) enhanced electrically stimulated release of [3H]NE from rat cortical slices. Both clonidine (1 μM) and nomifensine (10 μM) inhibited the effect of HP 749 (1 μM). The enhancement of [3H]NE release produced by the μ2 adrenergic antagonist, idazoxan (0.1 μM), was completely reversed by the μ2 agonist, clonidine (1 μM), but was not affected by the NE uptake inhibitor, nomifensine (10 μM). These results indicate that the HP 749 enhancement of electrically stimulated [3H]NE release is due, at least in part, to a combination of presynaptic μ2‐adrenergic receptor antagonism and NE reuptake blockade. These mechanisms may contribute to some of the adrenergic effects of HP 749.