α₂-Adrenoceptor Antagonists: Synthesis, Pharmacological Evaluation, and Molecular Modeling Investigation of Pyridinoguanidine, Pyridino-2-aminoimidazoline and Their Derivatives

Abstract

We have previously identified phenylguanidine and phenyl-2-aminoimidazoline compounds as high affinity ligands with conflicting functional activity at the α2-adrenoceptor, a G-protein-coupled receptor with relevance in several neuropsychiatric conditions. In this paper we describe the design, synthesis, and pharmacological evaluation of a new series of pyridine derivatives [para substituted 2- and 3-guanidino and 2- and 3-(2-aminoimidazolino)pyridines, disubstituted 2-guanidinopyridines and N-substituted-2-amino-1,4-dihydroquinazolines] that were found to be antagonists/inverse agonists of the α2-adrenoceptor. Furthermore, the compounds exert their effects at the α2-adrenoceptor both in vitro in human prefrontal cortex tissue and in vivo in rat brain as shown by microdialysis experiments. We also provide a docking study at the α2A- and α2C-adrenoceptor subtypes demonstrating the structural features required for high affinity binding to the receptor.

Prediction of Aqueous pKaValues for Guanidine-Containing Compounds Using Ab Initio Gas-Phase Equilibrium Bond Lengths

“…The test compounds discussed in sections 4.1.3 and 4.1.4 were synthesized previously, as reported by Rozas and co-workers ( ph1–ph10 and py1–py7 ) 37,38 and Dardonville and co-workers ( ph11–ph15 , 1 , 2a , b–5a , b , and 6h ). 25,39 The substitution patterns of the test set include meta- and para-substituted compounds.…”

“…The test compounds discussed in sections and were synthesized previously, as reported by Rozas and co-workers ( ph1–ph10 and py1–py7 ) , and Dardonville and co-workers ( ph11–ph15 , 1 , 2a , b–5a , b , and 6h ). , The substitution patterns of the test set include meta- and para-substituted compounds. The p K a values were measured by both the potentiometric (pH-metric) and spectrophotometric (UV-metric) methods of p K a determination.…”

1,3‐Diazepine: A privileged scaffold in medicinal chemistry

“…A first modification was realized by incorporating the guanidine function to obtain the 3,4‐dihydroquinazolin‐2‐amine derivative 58 . The stiffening brought to the structure led to a decrease in affinity for the receptor 254 . McMullan therefore proposed to introduce a supplementary carbon atom to the guanidine ring to increase the system flexibility and thus insure better positioning of the compound within the receptor active site (1,3‐benzodiazepine derivatives).…”

Synthesis of Bicyclic and Tricyclic Chiral Guanidinium Salts by an Intramolecular Alkylation Approach

“…As can be seen from the works of Moyer and Rozas, conformationally rigid guanidine scaffolds can be obtained by construction of acyclic species stabilized by intramolecular hydrogen bonds. Nevertheless, the synthesis of saturated bicyclic guanidine derivatives remains the most obvious approach to such molecules with desired geometric properties, and also enables entry to chiral guanidine derivatives by using readily available amino acids.…”