Highly Potent 1-Aminocyclohexane-1-Carboxylic Acid Substituted V₂Agonists of Arginine Vasopressin

Abstract

The synthesis and some pharmacological properties of two sets of analogues, one consisting of six peptides with 1-aminocyclohexane-1-carboxylic acid (Acc) in position 2 and the other with the amino acid in position 3, have been described. All the peptides were tested for their pressor, antidiuretic, and uterotonic in vitro activities. The Acc(2) modification has been shown to selectively modulate the activities of the analogues. Four of the compounds were highly potent antidiuretic agonists with different pressor and uterotonic activities. On the other hand, the 3-substituted counterparts failed to exhibit any of the activities. One exception was provided by the [Mpa(1),Acc(3),Val(4),D-Arg(8)]VP analogue, which exhibited antidiuretic activity matching that of AVP, yet, unlike AVP, it was fairly selective.

Arginine vasopressin and its analogues – The influence of position 2 modification with 3,3-diphenylalanine enantiomers. Highly potent V2 agonists

“…This finding supports our previous results showing that single substitution with some bulky residues may result in quite potent antagonists of OT receptors [44]. Such substitution is clearly disadvantageous when applied to antagonists of V 1a receptors, as has been documented in our previous paper [25]. …”

“…Our studies included among others the modification of AVP and some of its analogues with Acc and Apc, which resulted in compounds having high antidiuretic potency, decreased pressor activity and either no activity or low oxytocin antagonizing activity in the uterotonic in vitro tests [24][25][26].…”

“…We demonstrated that the arginine vasopressin analogues modified at position 2 with either L or D b-(1-naphthyl)-alanine were moderately potent and selective oxytocin antagonists in vitro [22], while [D-Arg 8 ]VP substituted at position 3 with b-(2-naphthyl)-alanine turned out to be a potent and selective antagonist of the pressor response to AVP [23]. We have also shown that introduction of either 1-aminocyclohexane-1-carboxylic acid (Acc, also known as Ac 6 c) or 1-aminocyclopentane-1-carboxylic acid (Apc, also known as Ac 5 c) into position 2 of AVP and some of its analogues resulted in compounds having high antidiuretic potency, low and graded pressor activity, and either no activity or low oxytocin antagonizing activity in the uterotonic in vitro tests [24][25][26]. Recently, we described some pharmacological activities of three analogues having bulky 3,3-diphenyl-L-alanine (Dip) in position 2 [27].…”

Solution‐, Solid‐Phase, and Fluorous Synthesis of β,β‐Difluorinated Cyclic Quaternary α‐Amino Acid Derivatives: A Comparative Study

“…[36] In particular, the 1-amino cyclohexanecarboxylic acid framework has been used in the design of cathepsin K inhibitors [37] and V 2 agonists of arginine vasopressin. [38] Treatment of (À)-10 with acetic anhydride followed by treatment with TBAF in THF gave the corresponding free carboxylic acid, which in turn was coupled with glycine ethyl ester to afford dipeptide (+)-12 in good yields (Scheme 5). Currently, we are working on the synthesis of peptidomimetic sequences with potential biological interest that bear the 1-amino 2,2-difluorocyclohexanecarboxylic acid unit.…”

Recent Advances in the Synthesis of Fluorinated Amino Acids

“…The 1-aminocyclohexanecarboxylic acid scaffold, for example, has been used in the design of a potent cathepsin K inhibitor [57] and V2 agonists of arginine vasopressin. [58] For these reasons and in view of the fact that incorporation of fluorine or fluorine-containing groups into compounds is widely used to improve the metabolic susceptibility of compounds, the synthesis of fluorinated cyclic amino acids has been receiving increasing attention in recent years.…”