Benzodiazepines & SAR (PDF)

Benzodiazepine, et al Benzodiazepines and benzodiazepine receptor ligands  Benzodiazepines  All benzodiazepines promote the binding of GABA to the GABAA receptor  The pharmacological properties of the benzodiazepines results from this interaction  Sedation/hypnosis  Decreased an...

Benzodiazepine, et al Benzodiazepines and benzodiazepine receptor ligands  Benzodiazepines  All benzodiazepines promote the binding of GABA to the GABAA receptor  The pharmacological properties of the benzodiazepines results from this interaction  Sedation/hypnosis  Decreased anxiety  Anterograde amnesia  Anticonvulsant  Muscle relaxation  That is they all have the ability to produce all these effects  Benzodiazepines  The therapeutic use of the individual compounds depends on the half life of the compound  Anticonvulsants generally have long half-lives and rapid entry into the CNS(1° for status epilepticus)  Those used for sleep would ideally have short half- lives, this is true for most  Anti-anxiety compounds generally have long half-lives  It has also been found that there are different subtypes of the GABAA which also may influence the efficiency of the compounds in the above categories  The GABAA receptor is a ligand gated ion channel that allows Chloride flux into the neuron  Benzodiazepines allow GABA to bind more efficiently  You get more bang for the buck  Benzodiazepines  Note on the previous slide the alpha is listed with an X  A number of different alpha proteins have been identified a1,a2, a3, a4, a5, a6.  The benzodiazepines only bind to the GABAA receptors that contain a1, a2, a3, a5  Based on compounds that show relatively selective action, it has been found that  Subtypes containing a1 are responsible for sedation/hyponosis  Subtypes containing a2 and a5 are possibly responsible for anxiolytic activity  Subtypes a1, a2, and a3 are possibly responsible for the anticonvulsant activity  Muscle relaxation maybe tied up with several subtypes that is  Benzodiazepines Compound Alpha 1 Alpha 2 Alpha 3 Alpha 5 Diazepam1 16 16 17 15 Clonazepam2 1.3 1.7 2 - Triazolam3 1.8 1.2 3 1.2 Ro15-4513 2.6 2.6 1.3 0.24 Zolipidem4 1.7 291 357 >15000 L-655-708 48 27 24 0.45 1. Non-selective, 2. Anticonvulsant, 3. Anxiolytic, 4.Hypnotic  Benzodiazepines SAR 1 7 4  Above is the general structure of a 1,4 benzodiazepine  An electron withdrawing group is required at the 7 position,  X= Cl, Br, F, CN, CF3 NO2  Stronger groups give more potent compounds  Trifluoromethyl and nitro are the most potent  Benzodiazepines SAR  Substitution at the 6, 8 or 9 position decreases activity  Benzodiazepines SAR 5  The aromatic ring at the 5 position is necessary ,  EWG orthro(#1) or di-orthro(#2) increase potency  Para substitution greatly decrease potency  Benzodiazepines SAR  Compounds without an aromatic ring at the 5 position have antagonist activity  Benzodiazepines SAR  Reduction of the 4,5 double bond or shifting to a 3,4 double bond decreases potency  Benzodiazepines SAR 1 2 3  Alkyl substitution at the 3 position decreases potency as in 1  Hydroxyl substitution at 3(#2) does not effect potency to any great extent but it does shorten the half-life. Compounds of this type are glucuronidated and excreted  Esters(3) are readily hydrolyzed to compound 2  Benzodiazepines SAR 4  3-carboxylic acids are pro-drugs,  readily undergo decarboxylation to 3-H compounds  Takes place in the acidic environment of the stomach  Benzodiazepines SAR  2-Carbonyl gives optimum activity, 2-thione, 2-imine and 2- methylamino are less potent  Benzodiazepines SAR  N1 substitution should be small, H, Methyl, Ethyl as in 1-3  Benzyl is more bulky and would be less active as is but would be converted to 3 on metabolism  Benzodiazepines SAR  Fused triazole and imidazole compounds show some selectivity for hypnosis and anxiolytic activity, Midazolam, triazolam and alprazolam  These compounds also have short half-lives, metabolism occurs via oxidation of the CH3 to the alcohol followed by glucuronide formation  Benzodiazepines  See the metabolism chart which is a separate handout.  A couple of things to note about the chart  A number of agents all go to the same final product oxazepam  Those at the end closes to glucuronidation all have fairly short half-lives and therefore are least likely to accumulate on multiple dosing.  The triazole and imidazole type compounds also have fairly short half-lives and do not accumulate  Non-Benzodiazepines agonist  Zolpidem Ambien ( AM good)  Rapid absorption food delays, onset 30 min after administration  Half life 2.5 h increased in liver disease  Duration 6-8 hours  Metabolized by 3A4 to inactive metabolite so no accumulation  92% protein bound  ADR: amnesia  Non-Benzodiazepines agonist  Zaleplon Sonata  30% bioavailable. Onset 1hr food delays  Metabolized by aldehyde oxidase to an inactive metabolite little CP450 involvement half-life 1 hour duration 6-8 h  60% protein bound  ADR Amnesia  Non-Benzodiazepines agonist  Eszopiclone Lunesta  S isomer of zopiclone  Rapid absorption peak in 1 hour food delays  50% protein binding  Metabolized by 3A4 AND 2E1 to one active ( desmethyl) and one inactive ( N-oxide) metabolites  Half-life 6h  ADR: headache, hallucinations anxiety, amnesia, Unpleasant taste (34%)  Now for something completely different  Ramelteon Rozerem ( Best for sleep onset problems)  Agonist at the melatonin receptors which control sleep-wake cycle and circadian rhythm  Onset 30 mins  Bioavailable is 1.8%  Metabolized by 1A2, first pass converts to active metabolite  Food delays absorption  82% protein bound  ADR: headache, depression, insomnia worsened