C-terminal deletions in agonistic and antagonistic analogues of vasopressin that improve their specificities for antidiuretic (V2) and vasopressor (V1) receptors

Article abstract of DOI:10.1021/jm00395a012

We report the solid-phase synthesis of 12 desGly and 12 desGly(NH₂) analogues of arginine-vasopressin (AVP), two highly selective antidiuretic (V₂) agonists, four vasopressor (V₁) antagonists, and five V₂/V₁ antagonists. The parent AVP agonists are (1) AVP, (2) 1-deamino[8-D-arginine]vasopressin (dDAVP), and (3) its 4-valine analogue, dVDAVP. The parent V₁ antagonists are (4) [1-(β-mercapto-β,β-pentamethylenepropionic acid)]arginine-vasopressin (d(CH₂)₅AVP), (5) d(CH₂)₅VDAVP, (6) [1-deaminopenicillamine,4-valine,8-D-arginine]vasopressin (dPVDAVP), and (7) d(CH₂)₅[Tyr(Me)]AVP. The parent V₂/V₁ antagonists are (8) d(CH₂)₅[D-Phe²,Ile⁴]AVP, (9) d(CH₂)₅[D-Phe²]VAVP, (10) d(CH₂)₅[D-Tyr(Et)²]VAVP, (11) d(CH₂)₅[Tyr(Et²]VAVP, and (12) d(CH₂)₅[D-Ile²,Ile⁴]AVP. All 24 analogues were tested for agonistic and antagonistic activities in in vivo rat vasopressor and rat antidiuretic assays. The desGly and desGly(NH₂) analogues of 1-3 are either weak partial agonists or weak antagonists of the V₁ responses to AVP. Except for desGly(NH₂)AVP, which is a weak V₂ agonist, the remaining desGly and desGly(NH₂) analogues of 1-3 exhibit substantial V₂ agonism and are thus highly selective V₂ agonists. With antidiuretic activity of 321 units/mg, a resynthesized desGly(NH₂)dVDAVP is equipotent with AVP as a V₂ agonist. Thus our previously stated conclusion about the need for C-terminal CONH₂ for V₂ agonism is no longer valid. The four pairs of desGly/desGly(NH₂) analogues of the V₁ antagonists (4-7) all retained varying degrees of V₁ antagonism and some exhibited striking enhancements in anti-V₁/V₂ selectivity. Thus the desGly/desGly(NH₂) analogues of d(CH₂)₅Tyr(Me)AVP are highly potent V₁ antagonists/weak V₂ antagonists with anti-V₁/V₂ selectivities of 200 and 1200, respectively. The four pairs of desGly/desGly(NH₂) analogues of the V₂/V₁ antagonists (8-11) exhibited enhancements, full retention, or slight diminishment of both V₁ and V₂ antagonism, with the desGly analogue being usually the more potent of each pair. The desGly and desGly(NH₂) analogues of d(CH₂)₅[D-Ile²,Ile⁴]AVP (12) exhibited anti-V₂/V₁ selectivities of 46 and about 440, respectively. These are the most selective V₂ antagonists reported to date. Many of these analogues could serve as useful pharmacological tools in studies on the roles of AVP in normal and pathophysiological circumstances.