Chemical syntheses and biological studies on dimeric chimeras of oxytocin and the V-2-antagonist, d(CH2)(5)[D-Ile(2),Ile(4)]arginine vasopressin

Parallel and antiparallel heterodimers have been synthesized that combine i nto a single molecule the neurohypophyseal hormone oxytocin and the potent vasopressin V-2-antagonist d(CH2)(5)[D-Ile(2),Ile(4)]arginine vasopressin, Solid-phase synthesis with N-alpha-9-fluorenylmethyloxycarbonyl (Fmoc) chem istry, featuring appropriate combinations of orthogonal protecting groups f or the thiols [S-(N-methyl-N-phenylcarbamoyl)sulfenyl (Snm); S-acetamidorme thyl (Acm); S-triphenylmethyl (Trt)], was used to assemble the required lin ear nonapeptide amide monomer intermediates, which were then brought togeth er in defined ways by solution reactions to provide the two heterodimers. T he first disulfide bridge was formed by a directed approach involving attac k by the free thiol of the 1-beta-mercapta-beta,beta-cyclopentamethylenepro pionic acid (Pmp) residue of one monomer onto the Snm group of a cysteine r esidue on the other monomer; the inverse directed strategy failed due to st eric hindrance. The second disulfide bridge was formed by iodine co-oxidati on of Cys(Acm) residues on adjacent chains. Biological studies revealed tha t both the parallel and antiparallel chimeras lack presser activity, have l ow uterotonic activity, and have diuretic activities comparable to that of the monomeric V-2-antagonist, Sodium excretion depends on experimental cond itions. Thus, with a 4% water load, both chimeras display effects similar t o that of an equimolar mixture of oxytocin and V-2-antagonist, i.e., lower sodium excretion than that resulting from administration of oxytocin alone but higher than that when V-2-antagonist was administered alone. However, w hen no water load was used, the parallel chimera proved to be more effectiv e in promoting sodium excretion than either oxytocin alone or an equimolar mixture of oxytocin and V-2-antagonist.