Info

Data from ref. 44.

Data are presented here and in subsequent tables as EC50—the dose required for half maximal GH release from cultured rat pituitary cells as described in ref. 26.

Data from ref. 44.

Data are presented here and in subsequent tables as EC50—the dose required for half maximal GH release from cultured rat pituitary cells as described in ref. 26.

nist asperlicin (46). They modified and derivatized that core unit culminating in the synthesis of 18 with its remarkable IC50 = 0.08 nM as a CCK-A receptor antagonist (47). Importantly, the work of Evans et al. (45) demonstrated that the privileged structure strategy for biogenic amine antagonists could also be applied to peptide ligands (Fig. 6).

The Privileged Structure Concept

The recognition of conserved structural units in receptor antagonists originated with Ariens et al. (48). They noted the occurrence of a hydrophobic, double-ring motif in many biogenic amine antagonists and suggested that these antagonists bind in "accessory binding sites" close to the "active sites" of receptors. The example of chlorpromazine that has anticholinergic, antihistaminic and a-adrenergic blocking actions was cited by them with implied similarity in the proposed accessory binding sites of these receptors. As a corollary, attaining excellent receptor specificities is often a problem that must be addressed while derivatizing privileged structures.

The spiroindanylpiperidine component of 10 was considered by us to be a privileged structure since ligands containing it were also known and subsequently published for the oxytocin (43) and sigma receptors (49). And more recently antagonists that incorporate it have been described for the neurokinin (NK)-1 (50) and NK-2 (51) receptors and in dual NK-1 and NK-2 antagonists (52). In addition agonists of the C5a receptor have been described based on spiropiperidines (53).

Was this article helpful?

0 0

Post a comment