Synthesis and structure-activity relationships of novel dipeptides and reduced dipeptides as ligands for melanocortin subtype-4 receptor.

A series of benzylic piperazines (e.g., 4 and 5) attached to an 'address element', the dipeptide H-D-Tic-D-p-Cl-Phe-OH, 3 has been identified as ligands for the melanocortin subtype-4 receptor (MC4R). We describe herein the structure-activity relationship (SAR) studies on the N-terminal residue of the 'address element'. Several novel dipeptides and reduced dipeptides with high MC4R binding affinities and selectivity emerged from this SAR study.

Privileged structure-based ligands for melanocortin receptors-tetrahydroquinolines, indoles, and aminotetralines.

Substitution of the aryl sulfonamide moiety contained in MC4 agonist 1 with bicyclic heterocycles and aminotetralines produced compounds with MC4 activity. The heterocycles represent alternative privileged structures to that contained in 1. Compounds in which the polar group of the privileged structure was displayed in an endocyclic fashion were not as active as the parent agonist 1, while those with an exocyclic polar group afforded activity competitive with 1.

Competitive Intramolecular/Intermolecular Chelation Options Operative during Indium-Promoted Additions to Pyridyl Aldehydes and to Glyoxylic Acid under Aqueous Conditions.

The stereochemical course of the 1,2-addition of six allylindium reagents to 2- and 3-pyridinecarboxaldehyde and to glyoxylic acid has been investigated in order to assess the level and direction of diastereoselectivity in these coupling reactions. When 2-PyCHO is involved, the results strongly suggest that the ring nitrogen becomes chelated to the indium atom in the aqueous environment. One striking observation is the crossover in stereoselectivity seen relative to the use of 3-PyCHO. A second revealing fact is the significantly faster rate of reaction of 2-PyCHO, as long as steric effects are not allowed to interfere. The varying product distributions observed in the latter experiments are attributed to other control elements such as intramolecular chelation within the indium reagent and nonbonded steric restrictions resident in either or both reaction partners. In the absence of extramolecular chelating events (e.g., when 3-PyCHO is involved), adherence to Felkin-Anh transition-state alignments is presumably exercised. The previous working assumption that indium(III) is capable of chelation to flanking heteroatomic centers in water is supported by the present investigation.