Nonpeptidic Ligands for Peptide-Activated G Protein-Coupled Receptors

Abstract

constants (pK a 's 3.1-4.8 (tetrazoles), 9.8-10.2 (sulfonamides) 65 ). The different acidities might influence the success of compounds in ViVo, since those containing tetrazole but not sulfonamide substituents are presently used in the clinic.Compounds 2-14 were designed from 1 by aligning their imidazoles with that of His6 in the [Sar]-AII structure. 66 Subsequent modification gave the biphenylimidazole scaffold found in most of the antihypertensive 'sartans' (pharmacokinetic properties in Table 2). Structure-activity relationship Chart 1

Neuropeptide Receptors in Pain Circuitries: Useful Targets for CNS Imaging with Non-Peptide Ligands Suitable for PET?

“…Olcegepant has been developed from a dipeptide mimetic R1-(3,5-dibromo-Tyr)-LYS-R2. As revealed by analysis of the structure-activity-relationships, similar structures were achieved when the N-terminal functionality was aromatic and was separated from the 3,5-dibromo-Tyr moiety, whereas for the C-terminal region a rigid negative polarizing group linked to a pyridine was favorable [149] [152]. These developments resulted in a high affinity CGRP antagonist (IC 50 , 0.014 nM) which could inhibit neurogenic vasodilation in a surrogate animal model of migraine.…”

“…One first highly specific of these substances was CP 96345 (22, Figure 7 and Table 2). More precisely it was the (2S,3S)-enatiomer which showed the high affinity of 4 nM [152] [213]. However, the compound had a 100fold higher affinity to the NK1 receptor in rat and mouse than in humans and other species.…”

“…(W74) suggested to be of key importance for the characteristic binding properties of hCGRP [156]. The difference of the amino acid in this position has been made responsible for low homology between the RAMP-1 proteins of primates and humans and that of rats (with Lys74; [152]. Olcegepant has been developed from a dipeptide mimetic R1-(3,5-dibromo-Tyr)-LYS-R2.…”

“…The substance had a 100fold higher selectivity for hCGRP compared to the rat receptor [149] [152] [154]. The agonist CGRP2 (17) ( Figure 5 and Table 2) differs only in few structural features from olcegepant while SB 273779 (13) (Figure 4) [152] avoids the high species selectivity but also the high affinity of these substances.…”

Synthesis and cytotoxicity studies of 1-propenyl-1,3-dihydro-benzimidazol-2-one

“…Benzimidazolone scaffold is one of the key scaffolds of a variety of heterocyclic compounds that play crucial roles in the modulation of a number of biologically important pathways [8][9][10][11]. Thus, benzimidazole and its derivatives representing a major class of nitrogencontaining heterocycles have gained an important role in the drug discovery [12][13][14][15]. The biological importance of benzimidazole derivatives is due to their structural resemblance to the naturally occurring nucleotides.…”