Linked Life Data

2960812

Source:http://linkedlifedata.com/resource/pubmed/id/2960812

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
1988-1-21
pubmed:abstractText
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-(beta-mercapto-beta,beta-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 Thus our previously stated conclusion about the need for C-terminal CONH2 for V2 agonism is no longer valid.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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:volume
30
pubmed:owner
NLM
pubmed:authorsComplete
N
pubmed:pagination
2245-52
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
1987
pubmed:articleTitle
C-terminal deletions in agonistic and antagonistic analogues of vasopressin that improve their specificities for antidiuretic (V2) and vasopressor (V1) receptors.
pubmed:affiliation
Department of Biochemistry, Medical College of Ohio, Toledo 43699.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.