Tomoichi Shinohara

Characterization of a novel nonpeptide vasopressin V2‐agonist, OPC‐51803, in cells transfected human vasopressin receptor subtypes

We discovered the first nonpeptide arginine‐vasopressin (AVP) V2‐receptor agonist, OPC‐51803. Pharmacological properties of OPC‐51803 were elucidated using HeLa cells expressing human AVP receptor subtypes (V2, V1a and V1b) and compared with those of 1‐desamino‐8‐D‐arginine vasopressin (dDAVP), a peptide V2‐receptor agonist. OPC‐51803 and dDAVP displaced [3H]‐AVP binding to human V2‐ and V1a‐receptors with Ki values of 91.9±10.8 nM (n=6) and 3.12±0.38 nM (n=6) for V2‐receptors, and 819±39 nM (n=6) and 41.5±9.9 nM (n=6) for V1a‐receptors, indicating that OPC‐51803 was about nine times more selective for V2‐receptors, similar to the selectivity of dDAVP. OPC‐51803 scarcely displaced [3H]‐AVP binding to human V1b‐receptors even at 10−4 M, while dDAVP showed potent affinity to human V1b‐receptors with the Ki value of 13.7±3.2 nM (n=4). OPC‐51803 concentration‐dependently increased cyclic adenosine 3′, 5′‐monophosphate (cyclic AMP) production in HeLa cells expressing human V2‐receptors with an EC50 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 V2‐antagonist, OPC‐31260. At 10−5 M, OPC‐51803 did not increase the intracellular Ca2+ concentration ([Ca2+]i) in HeLa cells expressing human V1a‐receptors. On the other hand, dDAVP increased [Ca2+]i in HeLa cells expressing human V1a‐ and V1b‐receptors in a concentration‐dependent fashion. From these results, OPC‐51803 has been confirmed to be the first nonpeptide agonist for human AVP V2‐receptors without agonistic activities for V1a‐ and V1b‐receptors. OPC‐51803 may be useful for the treatment of AVP‐deficient pathophysiological states and as a tool for AVP researches.

Practical stereoselective synthesis of (2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)acetic acid

Highly enantioselective asymmetric hydrogenation of readily accessible olefins, (E)- and (Z)-[1-(toluene-4-sulfonyl)-1,2,3, 4-tetrahydro-1H-benzo[b]azepin-5-ylidene]acetic acid (4a and 4b, respectively) and [1-(toluene-4-sulfonyl)-2, 3-dihydro-1H-benzo[b]azepin-5-yl]acetic acid (4c), is presented as an efficient and straightforward route to (R)-[1-(toluene-4-sulfonyl)-2,3,4, 5-tetrahydro-1H-benzo[b]azepin-5-yl]acetic acid [(R)-1] which is a key intermediate for the synthesis of non-peptide AVP V2-agonist. Hydrogenation of carboxylic acid 4c gave (R)-1 in quantitative yield and 85% ee using Ru(OAc)2[(S)-H8-BINAP], a Ru(II) complex of a partially hydrogenated BINAP (H8-BINAP), as a catalyst. When (R)-1 of 76% ee was transformed into the corresponding isopropylamide 6, pure enantiomer (R)-6 was obtained in 75% yield by recrystallization from MeOH.