The change of selectivity and the induction of antagonism by the insertion of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) in the second position of several opioid peptides have led to the interpretation of Tyr-Tic as a specific message domain for delta-opioid antagonists and to the discovery of dipeptides with substantial opioid activity. Selectivity and activity increase enormously when Tyr is substituted by 2',6'-dimethyl tyrosine (Dmt), hinting that the side chain of Dmt fits a hydrophobic cavity of the receptor very tightly and precisely. We have investigated the specificity of this fit by systematic changes of the substituents on the aromatic ring of ryr. Mono- and disubstitutions different from 2',6'- invariably lead to catastrophic decreases of activity. The only substitution compatible with retention of substantial antagonism is 2-methyl. An analysis of the conformational properties of all analogues reveals that substitutions do not affect the global shape of the molecule significantly. Accordingly, it is possible to use the shape of the different side chains to map the hydrophobic cavity of the receptor. The resulting complementary image is funnel shaped.

Several synthetic endothelin (ET) analogues of the C-terminal ET hexapeptide (ET16-21) were analyzed by radio-receptor competition binding assays and biologic activity using both ETA and ETB receptor subtypes. In addition, we produced a hybridoma monoclonal antibody, anti-ET15-21, that appeared to crossreact with the entire ET molecule and was able to neutralize its biologic activity. Antibody binding was measured with competition enzyme-linked immunosorbent assays and a surface plasmon resonance-based biosensor (BIA technology). The ET16-21 moiety was modified with systematic replacement of each residue by alanine (Ala-scan). Whereas the C-terminal residues (Asp18, Ile20, and particularly Trp21) were very important for both receptor binding and immunologic activity, Ala substitution in positions 16, 17, and 19 hardly affected such activities. Analysis of another series of synthetic ET16-21 analogues with the His16 residue replaced by a non-amino-acidic block confirmed that the last two C-terminal residues are essential for receptor and antibody binding, whereas the central region of this hexapeptide is much more tolerant to modification. However, a critical steric conformation of the active hexapeptide is necessary.

Durch 1,3‐dipolare Cycloaddition werden aus Benzoylacetylen (I) und Azidoessigsäureethylester (II) die isomeren Benzoyl‐triazolyl‐essigsäureester (III) und (IV) erhalten, während das dritte Isomere (VI) aus Benzoyltriazol (V) zugänglich ist.

In striaturn and several other tissues, a guanine nucleotide binding protein (G,) couples A, adenosine receptor to activation of adenylyl cyclase. We have examined the effect of guanine nucleoside diphosphate and triphosphate on 13H]CGS 21680 binding to A, , adenosine receptors of rat striaturn. Both GDP and GTP inhibited specific 13H]CGS 21680 binding to rat striatal membranes by 50% at about 0.1 mM. GMP was inhibitory only at higher concentrations, and the estimated I C, , value was greater than 1 mM. The nonhydrolyzable analog of GTP, Gpp(NH)p, was as potent as GTP with an I C, , value of approximately 86 FM. These results suggest that the regulation of adenosine receptor binding properties by guanine nucleotides i s independent of G, activation, since inhibition of agonist binding is achieved by addition of both guanine nucleoside diphosphate and triphosphate. o 1993 Wiley-Liss, Inc.

The nitro compounds (IIIa), (IVa), (VII), and (VIII) are synthesized in different ways and converted into numerous derivatives, e.g. (IIIb) ‐ (IIIf) and (IVb) ‐ (IVf) by a well‐known method.