The discovery of a series of nonpeptide arginine vasopressin V(2) receptor agonists is described. After identifying the aniline derivative 8 as our lead compound from the metabolites of compound 7 that showed antidiuretic activity by po administration to Brattleboro rats, improvements in the in vitro potency involving evaluations of the structural requirements for agonist action and optimizing the structure of the benzoyl moiety have been intensively undertaken. These studies led to compounds 16g, 19a, and 23b,h,i that show potent agonist activity for the V(2) receptor.

1 We discovered the ®rst nonpeptide arginine-vasopressin (AVP) V 2 -receptor agonist, OPC-51803. Pharmacological properties of OPC-51803 were elucidated using HeLa cells expressing human AVP receptor subtypes (V 2 , V 1a and V 1b ) and compared with those of 1-desamino-8-D-arginine vasopressin (dDAVP), a peptide V 2 -receptor agonist. 2 OPC-51803 and dDAVP displaced [3 H]-AVP binding to human V 2 -and V 1a -receptors with K i values of 91.9+10.8 nM (n=6) and 3.12+0.38 nM (n=6) for V 2 -receptors, and 819+39 nM (n=6) and 41.5+9.9 nM (n=6) for V 1a -receptors, indicating that OPC-51803 was about nine times more selective for V 2 -receptors, similar to the selectivity of dDAVP. OPC-51803 scarcely displaced [3 H]-AVP binding to human V 1b -receptors even at 10 74 M, while dDAVP showed potent anity to human V 1b -receptors with the K i value of 13.7+3.2 nM (n=4). 3 OPC-51803 concentration-dependently increased cyclic adenosine 3', 5'-monophosphate (cyclic AMP) production in HeLa cells expressing human V 2 -receptors with an EC 50 value of 189+14 nM (n=6). The concentration-response curve for cyclic AMP production induced by OPC-51803 was shifted to the right in the presence of a V 2 -antagonist, OPC-31260. ] i in HeLa cells expressing human V 1a -and V 1b -receptors in a concentration-dependent fashion. 5 From these results, OPC-51803 has been con®rmed to be the ®rst nonpeptide agonist for human AVP V 2 -receptors without agonistic activities for V 1a -and V 1b -receptors. OPC-51803 may be useful for the treatment of AVP-de®cient pathophysiological states and as a tool for AVP researches.

The synthesis and evaluation of both the (R)- and (S)-enantioisomers about the 5-position on a tetrahydro-1H-1-benzazepine derivative were described. The absolute configuration of the (R,R)-isomer (10) was determined by X-ray crystallographic analysis. After evaluation of both enantiomers (compounds R-2, S-2) for binding affinity, cAMP accumulation, and an in vivo study using Brattleboro rats, R-2 showed more potent activity as a V(2) receptor agonist than S-2.

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