Abstract

Pravadoline is a novel cyclooxygenase-inhibiting analgesic with a preclinical profile of activity in vivo clearly distinct from that of other cyclooxygenase inhibitors. The purpose of the present study was to assess the possibility that pravadoline possesses pharmacologic actions in addition to inhibition of cyclooxygenase. The data demonstrate that pravadoline inhibits neuronally stimulated contractions of the guinea pig ileum and mouse vas deferens preparations. These actions of pravadoline are not shared by known cyclooxygenase inhibitors, but are mimicked by close structural analogs of pravadoline devoid of the ability to inhibit prostaglandin formation. Some structural analogs were inhibitory also in the rat vas deferens preparation. The inhibitory effects of pravadoline and a representative noncyclooxygenase-inhibiting analog in isolated tissue preparations are not mediated by an interaction with muscarinic cholinergic, adrenergic (alpha-1 or alpha-2), serotonin (5-hydroxytryptamine2 or 5-hydroxytryptamine3), opioid (mu, kappa or delta), purinergic (P1), neurokinin-1, bradykinin (B2) or prostaglandin (E2) receptors. It is concluded that pravadoline and aminoalkylinodole analogs are inhibitory in several bioassay systems via a presynaptic mechanism which does not involve inhibition of cyclooxygenase, or the activation or inhibition of several known receptors. The relevance of this mechanism to aminoalkyindole actions in vivo is the subject of future studies.