Abstract

The pharmacokinetic-pharmacodynamic (PK-PD) correlations of seven prototypical 5-HT_1A agonists were analyzed on the basis of a recently proposed semi-mechanistic PK-PD model for the effect on body temperature. The resulting concentration-effect relationships were subsequently analyzed on the basis of the operational model of agonism to estimate the operational affinity (pK_A) and efficacy (log τ) at the 5-HT_1A receptor in vivo. The values obtained in this manner were compared with estimates of the affinity (pK_i) and intrinsic efficacy (log[agonist ratio]) in a receptor-binding assay. Between 5-HT_1A agonists wide differences in in vivo affinity and efficacy were observed, with values of the pK_A ranging from 5.67 for flesinoxan to 8.63 for WAY-100,635 [N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-2-pyridinyl-cyclohexanecarboxamide] and of the log τ ranging from –1.27 for WAY-100,135 [N-(1,1-dimethylethyl)-4-(2-methoxyphenyl)-α-phenyl-1-piperazine-propanamide] to 0.62 for R-(+)-8-hydroxy-2-[di-n-propylamino)tetralin. Poor correlations were observed between the in vivo receptor affinity (pK_A) and the affinity estimates in the in vitro receptor binding assay (pK_i; r² = 0.55, P > 0.05), which could in part be explained by differences in blood-brain distribution. In contrast, a highly significant correlation was observed between the efficacy parameters in vivo (log τ) and in vitro (log [agonist ratio]; r² = 0.76, P < 0.05). Thus by combining the previously proposed semi-mechanistic PK-PD model for the effect on body temperature with the operational model of agonism, a full mechanistic PK-PD model for 5-HT_1A receptor agonists has been obtained, which is highly predictive of the in vivo intrinsic efficacy.