Potent V2 vasopressin antagonists with structural changes at their C-terminals

A variety of structural changes were made in the C-terminals of four potent antidiuretic (V2) antagonists. The parent analogs were all derivatives of [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid)]arginine-vasopressin, d(CH2)5AVP, namely d(CH2)5[D-Phe2,Ile4]AVP, d(CH2)5[D-Ile2,Ile4]AVP, d(CH2)5[D-Tyr(Et)2, Val4]AVP and d(CH2)5[D-Tyr(Et)2,Ile4]AVP. A number of amino acid amides were substituted for the C-terminal 9-glycinamide without reducing their V2-antagonistic potencies in rats. Many non-amino acid structures were also tolerated at the C-terminals of these antagonists and this end of these peptides can be prolonged without interfering with antagonistic potencies. Such altered V2-antagonists may be useful for the development of radioactive ligands, affinity labels and in affinity columns for studies on antidiuretic receptors. These C-terminal modifications also provide useful information for the further development of potent and specific V2-antagonists which can be valuable pharmacological tools and also promise to become useful clinically for the treatment of excessive water retention.     

Studies on the total synthesis of an A7,B7-dicarbainsulin. III. Assembly of segments and generation of biological activity

As a further contribution to the synthesis of an insulin analogue with a stable A7-B7 interchain bond, the synthesis of A(8-21) by solution methods, and of B(9-25) as well as [7-(2,7-diaminosuberic acid)]B(1-8) by solid phase methods is described. In the latter compound, the amino group of the diaminosuberic acid residue was acylated with A(1-6), and the resulting "U-peptide" sequentially elongated with the C-terminal A- and finally B-chain sequences. The conversion of the product into the disulfide moiety gave a mixture which could not be resolved by currently available methods. However, the low biological activity of the crude product indicates that the A7-B7 disulfide bond is not crucially important for the activity of insulin.     

Sesquiterpene ketones from geranium macrorrhizum

Two novel stereoisomeric tricyclic sesquiterpene ketones were isolated from Geranium macrorrhizum.     

Design of peptide oxytocin antagonists with strikingly higher affinities and selectivities for the human oxytocin receptor than atosiban.

The peptide oxytocin (OT) antagonist atosiban, approved for tocolytic use in Europe (under the tradename Tractocile), represents an important new therapeutic advance for the treatment of premature labor. This paper presents some new peptide OT antagonists which offer promise as superior tocolytics. The solid phase synthesis is reported of four pairs of L and D-2-naphthylalanine (L/D-2Nal) position-2 modified analogs of the following four oxytocin (OT) antagonists: des-9-glycinamide [1-(beta-mercapto-beta,beta-pentamethylene propionic acid), 2-O-methyltyrosine, 4-threonine]ornithine-vasotocin (desGly-NH(2),d(CH(2))(5)[Tyr(Me)(2),Thr(4)]OVT) (A); the Tyr-NH(2) (9) analog of (A), d(CH(2))(5)[Tyr(Me)(2),Thr(4),Tyr-NH(2) (9)]OVT (B); the Eda(9) analog of (A), d(CH(2))(5)[Tyr(Me)(2),Thr(4),Eda(9)]OVT (C); and the retro COCH(2)Ph(4-0H)(10) modified analog of (C), d(CH(2))(5)[Tyr(Me)(2),Thr(4),Eda(9)<-- COCH(2)Ph(4-0H)(10)]OVT (D). The eight new analogs of A-D are (1) desGly-NH(2),d(CH(2))(5)[D-2Nal(2),Thr(4)]OVT, (2) desGly-NH(2),d(CH(2))(5)[2-Nal(2),Thr(4)]OVT, (3) d(CH(2))(5)[D-2Nal(2),Thr(4),Tyr-NH(2) (9)]OVT, (4) d(CH(2))(5)[2Nal(2),Thr(4),Tyr-NH(2) (9)]OVT, (5) d(CH(2))(5)[D-2Nal(2),Thr(4),Eda(9)]OVT, (6) d(CH(2))(5)[2Nal(2),Thr(4),Eda(9)]OVT, (7) d(CH(2))(5)[D-2Nal(2),Thr(4),Eda(9)<-- COCH(2)Ph(4-0H)(10)]OVT, (8) d(CH(2))(5)[2Nal(2),Thr(4),Eda(9)<-- COCH(2)Ph(4-OH)(10)]OVT. Peptides 1-8 were evaluated for agonistic and antagonistic activities in in vitro and in vivo rat bioassays, in rat OT receptor (rOTR) binding assays and in human OT receptor (hOTR) and human vasopressin (VP) vasopressor (V(1a)) receptor (hV(1a)R) binding assays. Also reported are the hOTR and hV(1a)R affinity data for atosiban and for B. None of the eight peptides exhibit oxytocic or vasopressor agonism. Peptides 1-8 exhibit weak antidiuretic agonism (activities in the range 0.014-0.21 U/mg). Peptides 1-6 exhibit potent in vitro (no Mg(2+)) OT antagonism (anti-OT pA(2) values range from 7.63 to 8.08). Peptides 7 and 8 are weaker OT antagonists. Peptides 1-6 are all OT antagonists in vivo (estimated in vivo anti-OT pA(2) values in the range 6.94-7.23). Peptides 1-8 exhibit vasopressor antagonism, anti-V(1a) pA(2) values in the range 5.1-7.65. Peptides 1-8 exhibit high affinities for the rOTR (K(i) values = 0.3-7.8 nM). Peptides 1-4 and B exhibit surprisingly very high affinities for the hOTR; their K(i) values are 0.17, 0.29, 0.07, 0.14 and 0.59 nM, respectively. Peptides 1-4 and B exhibit respectively 449, 263, 1091, 546 and 129 times greater affinity for the hOTR than atosiban (K(i) = 76.4 nM). Peptides 1-4 exhibit high affinities for the hV(1a)R (K(i)s = 1.1 nM, 1.3 nM, 0.19 nM and 0.54 nM, all higher than the hV1(a)R affinities exhibited by atosiban (K(i) = 5.1 nM) and by B (K(i) = 5.26 nM). Because of their strikingly higher affinities for the hOTR than atosiban, peptides 1-4 and B exhibit gains in anti hOT/anti hV(1a) receptor selectivity compared with atosiban of 93, 64, 39, 56 and 127, respectively. These OT antagonists are thus promising candidates for development as potential new tocolytic agents.     

Discovery and design of novel vasopressin hypotensive peptide agonists

This presentation will trace the serendipitous discovery of novel vasopressin (VP) hypotensive agonists d(CH2)5[D-Tyr(Et)2,X3]VAVP (where X = Arg, Lys). These peptides were uncovered as part of an ongoing program aimed at the design of potent and selective VP antidiuretic (V2 receptor) antagonists. We will also present highlights of our subsequent preliminary studies seeking (i) to design high affinity radioiodinatable ligands for the localization and characterization of the putative VP vasodilatory (V1c?) receptor; (ii) to identify the structural features of selective and non-selective cyclic and linear VP and oxytocin (OT) antagonists of the V2 receptor, the vascular (V1a) receptor and of the uterine (OT) receptor required for hypotensive agonism and; (iii) to enhance hypotensive potency. These novel VP hypotensive agonists could serve as valuable research tools in studies on the roles of VP in blood pressure regulation and may also lead to the development of a new class of therapeutically useful antihypertensives.     

Review of the millipede family Opisotretidae (Diplopoda,Polydesmida), with descriptions of?new?species

The small, basically Oriental family Opisotretidae is rediagnosed, reclassified, and shown to comprise the following seven genera, all keyed: Carlotretus Hoffman, 1980, with two species, including Carlotretus triramus sp. n. from southern China; Corypholophus Attems, 1938, with two species, one in Vietnam, the other in the Ryukyus, Japan; Martensodesmus Golovatch, 1987, with eight species, all keyed, including Martensodesmus cattienensis sp. n. from southern Vietnam, as well as Martensodesmus bedosae sp. n. and Martensodesmus spiniger sp. n. from southern China; Opisotretus Attems, 1907, with seven species, all keyed, including Opisotretus beroni sp. n. and Opisotretus hagen sp. n., both from Papua New Guinea, Opisotretus deharvengi sp. n. from Sulawesi, Indonesia, and Opisotretus spinosus sp. n. from Nusakambangan Island, off Java, Indonesia; Opisthoporodesmus Silvestri, 1899, with six nominate species; Retrodesmus Chamberlin, 1945, with two species, i.e. the type-species Retrodesmus dammermani Chamberlin, 1945, from Java, Indonesia, revised from the holotype, and Retrodesmus cavernicola sp. n., from Papua New Guinea; and Solaenaulus Attems, 1940, with two species. Comments are presented on the family’s possible relationships and palaeogeographic history. Instead of being considered as the sole component of the superfamily Opisotretoidea, the Opisotretidae is believed here to form one of the families of the diverse superfamily Trichopolydesmoidea, perhaps the sister-group to, if not immediately derived from, the pantropical family Fuhrmannodesmidae. The origin of Opisotretidae, previously dated as far back as the Triassic (220 Ma) in relation to the fragmentation of eastern Gondwanaland, mainly in the region of present-day Indonesia, could have had nothing to do with Gondwanaland. Opisotretids might have originated in mainland Southeast Asia well within the Cenozoic, with subsequent dispersals along the Himalayas in the West and across Indonesia (including New Guinea) in the East, also reaching as far north as the Ryukyus, Japan and Guangxi, southern China.