A series of substituted 6-methoxysalicylamides were synthesized from their corresponding 2,6-dimethoxybenzamides by demethylation of one methoxy group with boron tribromide. Substituted 6-methoxysalicylamides having a lipophilic aromatic substituent in the 3-position para with respect to the methoxy group, e.g. a bromo or an iodo atom or an ethyl or a propyl group, and having an (S)-N-(1-alkyl-2-pyrrolidinyl)methyl moiety as the side chain were found to be potent blockers of [3H]spiperone binding in vitro and potent inhibitors of the apomorphine syndrome in the rat. Similar to remoxipride but in contrast to haloperidol, some of the substituted salicylamides show a 10-20-fold separation between the dose that inhibits hyperactivity and that which inhibits stereotypy. It was concluded that, besides the requirement of a lipophilic substituent in the position para to the methoxy group for antidopamine activity in vivo, the formation of a coplanar six-membered pseudoring involving the amide moiety and the methoxy group is a structural requirement for activity in vitro.
From salicyclic acid, the two enantiomers of N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2-methoxybenzamide (6b) were prepared in a five-step synthesis. With use of Heindel's triazene method for introduction of the radionuclide, the iodine-125-labeled substituted benzamide was obtained with a calculated specific activity of 136 Ci/mmol and 14% radiochemical yield. For the preparation of the iodine-125-labeled benzamide with higher specific activity, this method was unsuccessful and utilization of the corresponding tri-n-butyltin derivative was required. Treatment of the latter in dilute hydrochloric acid with sodium iodide-125 and chloramine-T gave [125I](S)-6b in 56% radiochemical yield and at least 97% radiochemical purity. The displacement of [125I](S)-6b and [3H](S)-sulpiride from their respective binding sites in striatal rat brain homogenates using various neuroleptic agents showed that (S)-6b has the same binding profile but more potent binding for dopamine D-2 receptors than has sulpiride. These experiments also indicate that the S enantiomer of 6b is a specific ligand (KD = 1.2 nM) for the D-2 receptor. Further, the octanol-water partition coefficient of (S)-6b as determined by reverse-phase high-performance liquid chromatography was found to be 40 times greater than that for sulpiride. Thus (S)-6b has a lipophilicity that will allow a relatively higher uptake into the brain compared to sulpiride. In vivo experiments with rats show that [125I](S)-6b penetrates readily into the brain and is preferentially localized in the striatum as compared to the cerebellum, the ratio of uptake being 7.2 to 1, 60 min after injection. These observations of good brain penetration and high affinity and selectivity for D-2 receptors indicate that the corresponding iodine-123-labeled benzamide may be a useful ligand for the noninvasive visualization study of dopamine D-2 receptor sites in vivo by single photon emission computed tomography.
A number of substituted N-[(1-benzyl-2-pyrrolidinyl)methyl]benzamides and -salicylamides have been prepared and investigated as dopamine D-2 receptor antagonists in vitro and in vivo. The affinity was found to be confined to the R enantiomer, in contrast to the corresponding N-ethyl or N-allyl derivatives. The X-ray structure of one of the compounds (15) confirmed the R stereochemistry. This compound (15) was found to adopt a solid-state conformation in which the 4-fluorobenzyl group is folded over the salicylamide moiety. Benzamides having a 2,3-dimethoxy substitution pattern (24 and 26) or salicylamides with a 5,6-dimethoxy grouping (21 and 22) were especially potent, in that they inhibited [3H]spiperone binding to rat striatal dopamine D-2 receptors in vitro with IC50 values of about 1 nM. The new compounds' ability to block apomorphine-induced stereotypies correlated with the affinity for the [3H]spiperone binding site. Higher dose levels were necessary to induce catalepsy than to block the apomorphine-induced responses. The influence of the aromatic substituents on the potency of substituted benzamides with three types of side chains, i.e. (R)-(1-benzyl-2-pyrrolidinyl)methyl, (S)-(1-ethyl-2-pyrrolidinyl)methyl and 1-benzyl-4-piperidinyl, was compared. The 3-bromo-5,6-dimethoxysalicylamide substitution pattern was found to be the most general since it gave very potent compounds in all series. The substituted (R)-N-[(1-(4-fluoro-benzyl)-2-pyrrolidinyl)methyl]benzamides (26) and -salicylamides (22) are suitable for development into 18F radioligands without altering the parent structure.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.