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Topic: Why is Lorazepam More Potent than Diazepam?  (Read 620 times)

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Offline sharbeldam

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Why is Lorazepam More Potent than Diazepam?
« on: October 29, 2019, 05:58:40 PM »
For instance it's clear to me why Clonazepam is more potent than Oxazepam for the following reasons:
1) NO2 at ring A is more electron withdrawing than Cl which raises the activity of the ring.
2) Hydroxyl group at ring B in oxazepam decreases potency
3) Chlorine in ring C at para position in Clonazepam increases potency.

But if we compare lorazepam with diazepam, the " score " of potency would be 2-1 in favour of diazepam since it has alkyl group instead of hydrogen in position 1 which raises potency (1 for diazepam), Lorazepam has hydroxy group in ring B which decreases potency and decrease t1/2( 2 for diazepam) but lorazepam has chlorine in the para position in ring C (1 for lorazepam).

So since lorazepam in real life is more potent than diazepam, does that mean that the halogen in para position in ring C is more important than ring B Substituents?

Thanks a lot in advanced.
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Offline rolnor

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Re: Why is Lorazepam More Potent than Diazepam?
« Reply #1 on: October 30, 2019, 04:06:52 AM »
The o-chloro in Lorazepam is probably adding affinity to the receptors, it can do so in different ways,
1. By better fit the receptor pocket
2. By forcing the phenylring in a diffirent confirmation that fits the receptor better
3. By making the molecule more lipophilic and this makes the afinnity the receptor stronger. This is partially contradicted by the fact that Lorazepam is missing the N-methylgroup compared to diazepam.
4. A combination of the above.

Offline sharbeldam

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Re: Why is Lorazepam More Potent than Diazepam?
« Reply #2 on: October 30, 2019, 04:48:04 AM »
Thank you!! how does the Cl exactly makes the molecule more lipophilic? since chlorine is electronegative , shouldnt that make it polar and hence less lipophilic?
« Last Edit: October 30, 2019, 07:48:32 AM by sharbeldam »
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Offline rolnor

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Re: Why is Lorazepam More Potent than Diazepam?
« Reply #3 on: October 30, 2019, 08:21:50 AM »
Thank you!! how does the Cl exactly makes the molecule more lipophilic? since chlorine is electronegative , shouldnt that make it polar and hence less lipophilic?

Benzene has watersolubility 1,8g/l, chlorobenzene 0,5g/l at 20°C.
It would be better to compare logP octanol/water but I dont find this data.
When chlorine is covalently bound in a molecule like this its mainly lipophilic in nature.

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