Throughout this application various publications are referred to by partial citations within parenthesis. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of these publications, in their entireties, are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
Molecular cloning efforts have provided primary amino acid sequence and signal transduction data for a large collection of serotonin receptor subtypes. These include five cloned 5-HT.sub.1 -like receptors, three cloned 5-HT.sub.2 receptors, and one 5-HT.sub.3 receptor. The 5-HT.sub.1 subfamily includes: 5-HT.sub.1A (Fargin, 1988; Kobilka, 1989), 5-HT.sub.1B /5-HT.sub.1D.beta. (Weinshank et al., 1991; Demchyshyn et al., 1992; Jin et al., 1992; Adham et al., 1992; Maroteaux et al., 1992; Voight et al., 1991), 5-HT.sub.1D.alpha. (Branchek et al. 1991; Hamblin and Metcalf, 1991; Weinshank et al., 1992), 5-HT.sub.1E (Levy et al., 1992; McAllister et al., 1992; Zgombick et al., 1992) and 5-HT.sub.1F (Adham et al., 1993). All five have been shown to couple to the inhibition of adenylate cyclase activity. The 5-HT.sub.2 family includes the 5-HT.sub.2 receptor (Pritchett et al., 1988), 5-HT.sub.1C (Julius et al., 1989) and 5-HT.sub.2F (Rat Stomach Fundus; Foquet et al., 1992; Kursar et al., 1992). These receptors all couple to phosphoinositide hydrolysis. The 5-HT.sub.3 receptor is a ligand-gated ion channel (Maricq et al., 1991).
Although this work represents enormous success, the absence of molecular biological information on the 5-HT.sub.4 receptors, which have been shown in native tissues to couple to the activation of adenylate cyclase as a primary mode of signal transduction (Dumius et al., 1988; Bockaert et al., 1990), is apparent. In a previous copending application (U.S. Ser. No., 971,690, filed Nov. 3, 1992), we reported the cloning of the first mammalian 5-HT receptor that couples to the stimulation of adenylate cyclase activity which we named 5-HT.sub.4B. The pharmacological properties of this receptor indicated that it was similar to a series of functionally defined 5-HT receptors described in the porcine vena cava (Trevethick et al., 1984), cat saphenous vein, coronary arteries (Cushing and Cohen, 1992), and several vascular dilatory effects (Mylecharane and Phillips, 1989). However, the classically defined 5-HT.sub.4 receptor remained to be cloned. We now report the cloning of the pharmacologically-defined 5-HT.sub.4 receptor which we have called 5-HT.sub.4A. This receptor also stimulates adenylate cyclase activity but unlike 5-HT.sub.4B, is sensitive to a series of benzamide derivatives which act as agonists or partial agonists at this subtype. The presence of this subtype in the brain, particularly in areas such as the hippocampus, indicates a potential role in cognitive enhancement. In addition, the 5-HT.sub.4 receptor has been described functionally in the heart, adrenal, bladder, and alimentary canal indicating potential roles in achalasia, hiatal hernia, esophageal spasm, irritable bowel disease, postoperative ileus, diabetic gastroparesis, emesis and other diseases of the gastrointestinal tract, as well as in cardiac, urinary, and endocrine function.