A Structure-Activity Relationship Study of Benzylic Modifications of 4-[1-(1-Naphthyl)ethyl]-1H-imidazoles on .alpha.1- and .alpha.2-Adrenergic Receptors

Abstract

The naphthalene analog of medetomidine (1), 4-[1-(1-naphthyl)ethyl]-1H- imidazole (2), is a highly potent, selective alpha 2-adrenoceptor agonist. We have initiated a structure-activity relationship study of the replacement of the methyl group on the carbon bridge between the naphthalene and imidazole rings of 2 with a hydrogen, hydroxy, methoxy, carbonyl, or trifluoromethyl group and compared their biological activities with medetomidine 1 and the optical isomers of 2. Analogs of 2 were antagonists of alpha 2A-adrenoceptor-mediated human platelet aggregation and agonists on alpha 1- and alpha 2-adrenoceptors in guinea pig ileum. The rank order and potencies of these analogs on platelets (alpha 2A-subtype) and guinea pig ileum (alpha 1-subtype) were nearly the same, whereas racemic and S-(+)-2, desmethyl, and hydroxy analogs were potent agonists on alpha 2-adrenoceptors in guinea pig ileum. With the exception of the desmethyl analog 5, none of the other analogs were as potent as the parent drug 2 on alpha 2A- (human platelets), alpha 1- (guinea pig ileum), or alpha 2- (guinea pig ileum) adrenergic receptor systems. As with analog 2, the desmethyl- and methoxy-substituted analogs retained a greater alpha 2/alpha 1-selectivity in both functional (agonist activity) and biochemical (receptor displacement) studies. Receptor binding studies indicate that S-(+)-2 possessed greater affinity than the R-(-)-isomer on both alpha 1- and alpha 2-adrenoceptors in rat brain. In addition, R-(-)-2 did not show agonist activity in alpha 2-adrenoceptors of guinea pig ileum and was 10-fold more potent than S-(+)-2 as an antagonist of alpha 2A-adrenoceptors in human platelets. Thus, the nature of the substituent and the chirality at the carbon bridge between the naphthalene and imidazole rings play an important role in maintaining potent alpha 2-adrenoceptor activity and high alpha 2/alpha 1-selectivity within the 4-substituted imidazole class.

Medetomidine Analogs as α2-Adrenergic Ligands. 2. Design, Synthesis, and Biological Activity of Conformationally Restricted Naphthalene Derivatives of Medetomidine

“…Additional biological evidence to support this hypothesis is that demethylated analogs of medetomidine and 5a were less potent at R 2 -adrenoceptors than their parent compounds. 7 In conclusion, from the results of this study, we have gained a new insight into the preferred conformation of imidazoles for interaction with R 2 -receptors. We propose that the nitrogen N 3 on the imidazole ring binds with Asp113 of the receptor.…”

“…7,27 Results are summarized in Table 2. On rat aorta, the R 1 -adrenoceptor responses were expressed as a percentage of the maximum contraction to 1 µM of phenylephrine.…”

“…However, this is not consistent with the experimental data which showed that replacement of the benzylic methyl group of 5a with a hydroxy group did not increase, but significantly decreased, the affinity at R-adrenoceptors. 7 In addition, the stereochemical configuration of these two classes at the benzylic carbon does not match. 33 This result suggests that the -rotamer of 21 may not be the appropriate conformation of phenethylamines, which is in agreement with hypotheses advanced by other authors.…”

Selective antiaggressive effect of an alpha‐2 adrenoceptor agonist naphthylmedetomidine in mice

“…dexmedetomidine). Results presented in these studies suggest that naphthylmedetomidine is more selective to a 2 -AR [Hong et al, 1994] and has higher affinity [Zhang et al, 1997] to a 2 -AR than medetomidine. a 2 -ARs are known to have a critical role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the central nervous system.…”

The effect of the novel alpha–2–adrenoceptor agonist naphthylmedetomidine on pulse rate, arterial blood pressure and sedation in rabbits

“…There are several studies describing its binding profile in comparison to medetomidine and its stereoisomers (e.g. dexmedetomidine) (Hong et al. 1994; Zhang et al.…”