Anxiolytics, Sedative-Hypnotics, and Amphetamine-Related Agents MEDCHEM

Vocabulary flashcards covering structure-activity relationships, pharmacokinetics, stereochemistry, and mechanisms of action for anxiolytics, sedative-hypnotics, orexin antagonists, and amphetamine-related stimulants.

Hypnotic Benzodiazepines

Benzodiazepines characterized by rapid absorption, high lipophilicity, and active metabolites that are slowly eliminated or absent.

Anxiolytic Benzodiazepines

Benzodiazepines characterized by slow absorption, low lipophilicity, and the presence of active metabolites.

Benzodiazepine Ring A SAR

Requires $\pi-\pi$ stacking and an electronegative substituent (such as $\text{Cl}$ or $\text{NO}_2$) at the 7-position to increase functional anxiolytic activity.

Benzodiazepine Ring B SAR

Requires a proton-accepting group; substitution at the 3-position or 4-N decreases antagonistic effects without decreasing agonistic affinities.

Benzodiazepine Ring C SAR

Not required for receptor binding, but planarity is necessary; ortho substitution with electron-withdrawing groups increases affinity, while para substitution is unfavorable.

1,2 Annelation

The addition of an electron-rich ring to positions 1 and 2 of a benzodiazepine ring system, resulting in high-affinity active compounds.

Benzodiazepine Active Stereoisomer

The S-isomer, which represents the active conformation between the two possible boat conformations of the 7-membered ring.

Eszopiclone (Lunesta)

A non-benzodiazepine cyclopyrrolone whose S-enantiomer is 50 times more active than its R-enantiomer.

Cyclopyrrolone Binding Site

A distinct binding site on the $\text{GABA}_A$ receptor complex allosteric to the benzodiazepine site, located within $4\,\text{\AA}$ of the GABA-BZ binding pocket.

Zaleplon Subtype Selectivity

A pyrazolopyrimidine that exhibits high affinity for $\alpha_1$-containing BZRs, showing 7-fold selectivity over $\alpha_2$ and 10-fold selectivity over $\alpha_5$.

5-Oxozaleplon

The major metabolite of zaleplon, formed via oxidation by aldehyde oxidase.

Imidazopyridines SAR

Subunit-selective $\alpha_1$ BZR/$\text{GABA}_A$ agonists such as Zolpidem; replacement of Cl with Me increases selectivity toward the $\alpha_1$-subtype.

Barbiturates Position 5 SAR

Requires disubstitution at position 5; branching, cyclic, aromatic, or halogen substituents increase lipophilicity.

Thiopental SAR

A thiobarbiturate in which replacement of C2=O with sulfur increases lipophilicity, leading to rapid onset and short duration of action as an anesthetic.

Melatonin Receptor Agonist Binding Interactions

Agonists whose 3-amide group binds to Ser110, Ser114, and Asn175 for agonistic effect, and whose 5-methoxy group binds to His195 and His208 for functional activity.

Ramelteon (Rozerem)

A rapidly absorbed melatonin receptor agonist that is metabolized primarily by CYP1A2.

Suvorexant

An orexin receptor antagonist containing a 5-chloro-benzoxazole ring, dispensed as the (7R)-enantiomer which has 10- to 20-fold greater functional potency at OX1R and OX2R compared to the (S)-enantiomer.

Amphetamine Mechanism of Action

Acts as a dopaminergic and noradrenergic agonist by increasing dopamine release and preventing its reuptake.

Amphetamine Phenyl Ring SAR

Any substitution on the phenyl ring decreases or abolishes amphetamine-like central stimulant activity.

Amphetamine Amine Substitution SAR

Activity follows the order $NH_2 > NHR > NR_2$; increasing alkyl chain length decreases activity, with methamphetamine (secondary amine) being a notable active exception.

Amphetamine $\alpha$-Substitution SAR

The $\alpha$-methyl group decreases susceptibility to metabolism by MAO; the S-isomer is more active than the R-isomer for central stimulant effects.

Amphetamine $\beta$-Substitution SAR

Addition of a $\beta$-OH group (e.g., ephedrine) decreases central stimulant effect due to low BBB penetration, whereas a $\beta$-keto group retains potency.

Modafinil

A stimulant agent with reduced abuse potential whose R-isomer acts as a potent $D_2$ partial agonist.

Cocaine Stereochemistry

A stimulant compound with eight possible stereoisomers, whose naturally occurring active stereoisomer is 1R, 2R, 3S.

Methylphenidate Metabolism

Undergoes enantiomeric hepatic metabolism where the (-)-form is metabolized faster to ritalinic acid; the (+)-enantiomer in the racemic mixture is the most active.