Novel 2-Phenylimidazo[1,2-a]pyridine Derivatives as Potent and Selective Ligands for Peripheral Benzodiazepine Receptors:  Synthesis, Binding Affinity, and in Vivo Studies

Abstract

The substituent effects at positions 6 and 8 (compounds 17-31) as well as at the amide nitrogen (compounds 32-40) of a series of 2-phenylimidazo[1,2-a]pyridineacetamides were evaluated at both central (CBR) and peripheral (PBR) benzodiazepine receptors. The structure-activity relationship studies detailed herein indicate the key structural features required for high affinity and selectivity for PBR. Substitution on the imidazopyridine nucleus at position 8 with lipophilic substituents and the presence of one chlorine atom at the para position of the phenyl ring at C(2) are crucial features for high binding affinity and selectivity toward PBR. A small subset of active ligands (i.e., 17, 20, 26, 34, and 35) were evaluated in vitro in Xenopus oocytes expressing cloned human GABA(A) receptors for their effects at CBR and in vivo for their ability to stimulate the synthesis of neurosteroids such as pregnenolone, progesterone, allopregnanolone, and allotetrahydrodeoxycorticosterone (THDOC). Compounds 17, 20, 26, and 34 markedly increased the levels of neuroactive steroids in plasma and cerebral cortex, unlike compound 35.

Steroid hormones and neurosteroids in normal and pathological aging of the nervous system

“…The possibility to increase the synthesis of neuroactive steroids has stimulated recent efforts to develop new more selective and efficient MBR ligands. Thus, derivatives of 2-phenyl-imidazol[1,2]pyrimidine bind MBR ligands with great affinity and selectivity, and when injected intraperitoneally, they significantly increase brain neurosteroid levels in castrated and adrenalectomized rats, in agreement with a stimulatory effect on brain neurosteroidogenesis Trapani et al, 1999). Among the pharmaceutical agents that have been recently developed to influence neurosteroid levels in the brain are the steroid sulfatase inhibitors.…”

Development of Ligands for the Peripheral Benzodiazepine Receptor

“…Based on results from radioligand binding assays, it was shown that disubstitution at 6-and 8-positions on the pyridine moiety with dichloro, dibromo, 6-CF 3 /8-chloro, 6-bromo/8-CH 3 or 6-CH 3 /8-Br substituents was a core feature in promoting selectivity for the PBR. Further SAR and structure-selectivity relationship (SSR) research helped explore the effects of modifying the alkyl groups attached to the amide functionality and resulted in the synthesis of an extended series of 2-phenyl-imidazo[1,2-a]-pyridine derivatives [66]. In 1999, three lead compounds from this series, (CB 54), were investigated for their agonistic effect on brain and plasma neurosteroid concentrations in normal and adrenalectomized-orchiectomized (ADX-ORX) rats [67].…”

“…Autoradiographic and biochemical studies revealed that the highest density binding of [ 3 H]DAA1106 in the brain was in the olfactory bulb, followed by the cerebellum and cerebral cortex [68]. [2-(4-chlorophenyl)imidazo [1,2-a]pyridin-3-yl)]acetamide, although displaying high PBR affinity (5-10 nM), was the only reported 2-phenyl-imidazo[1,2-a]-pyridine that failed to have any effect on neuroactive steroid concentration in cerebral cortex and is thus considered to be an antagonist [66]. These results proved that there was no direct association between affinity and selectivity for the PBR and functional steroidogenic activity.…”

Synthesis and structure of 3-arylidene and 3-hetarylidene-1,2-dihydro-3H-1,4-benzodiazepin-2-ones and their affinity toward CNS benzodiazepine receptors

“…The anesthetized animals were decapitated and the brain cortex, characterized by high BDR content, was rapidly removed in the cold. The analysis of the interaction of 1-17 with CBDR and PBDR was carried out according to previous procedures [17,18]. The affinity was found relative to the compounds at 1 µM to remove radioligands from sites of their specific binding with receptors.…”