PT  - JOURNAL ARTICLE
AU  - M L Cohen
AU  - W Bloomquist
AU  - J M Schaus
AU  - D C Thompson
AU  - A D Susemichel
AU  - D A Calligaro
AU  - I Cohen
TI  - LY353433, a potent, orally effective, long-acting 5-HT(4) receptor antagonist: comparison to cisapride and RS23597-190.
DP  - 1996 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 97--104
VI  - 277
IP  - 1
4099  - http://jpet.aspetjournals.org/content/277/1/97.short
4100  - http://jpet.aspetjournals.org/content/277/1/97.full
SO  - J Pharmacol Exp Ther1996 Apr 01; 277
AB  - Although many 5-HT (serotonin, 5-hydroxytryptamine)(4) receptor antagonists have been described, none possess the requisite oral activity and duration of action for a clinically effective therapeutic agent. The present report identifies LY353433 (1-(1-methylethyl)-N-[2-[4-[tricyclo[3.3.1.1(3,7)]dec-1-ylcarbo nyl) amino]-1-piperidinyl]ethyl]-1H-indazole-3-carboxamide), an indazole amide, as a high affinity antagonist at the 5-HT(4) receptor in the rat esophagus. LY353433 (10(-8), 3 x 10(-8), 10(-7) M) inhibited 5-HT-induced relaxation of carbamylcholine-contracted esophagus with greater potency than cisapride or RS23597-190, a known 5-HT(4) receptor ligand. Furthermore, RS23597-190 possessed marked agonist activity as did cisapride, whereas LY353433 did not relax the rat esophagus in concentrations up to 10(-5) M. LY353433 (up to 10(-5) M) did not possess appreciable affinity for adrenergic, dopaminergic, histaminergic, muscarinic or GABAergic receptors and, thus, was a highly selective 5-HT(4) receptor antagonist. In addition, LY353433 only slowly associated with an dissociated from the 5-HT(4) receptor, an attribute that conferred long-lasting 5-HT(4) receptor antagonist activity, in contrast to RS23597-190, which rapidly dissociated from the 5-HT(4) receptor. LY353433 dose-dependently inhibited the 5-HT(4) receptor-mediated ex vivo relaxation in the rat esophagus after either i.v. (0.1, 0.3 and 1.0 mg/kg) or p.o. (0.1, 0.3, 1.0 and 3.0 mg/kg) administration. Furthermore, the p.o. to i.v. dose ratio was approximately one, suggesting that LY353433 was well absorbed with excellent pharmacodynamics in the rat. LY353433 (0.3 mg/kg p.o.) blocked esophageal 5-HT(4) receptors ex vivo through 6 hr after p.o. dosing with responses returning to control by 16 hr, indicative of long duration receptor blockade. Lastly, in rats LY353433 was exceptionally safe because acute doses up to 300 mg/kg p.o. did not result in either symptoms or deaths. Thus, LY353433 is a potent, selective, orally effective, long-acting and safe 5-HT(4) receptor antagonist that is highly suitable for clinical use.