Selectivity uptake inhibitors

Mignot E, Renaud A, Nishino S, Arrigoni J, Guilleminault C, Dement WC (1993) Canine cataplexy is preferentially controlled by adrenergic mechanisms evidence using monoamine selective uptake inhibitors and release enhancers. Psychopharmacology 113 76-82... 

The norepinephrine selective uptake inhibitor reboxetine (21) is rapidly and completely absorbed, and is metabolized mainly by the cytochrome p450 3A4 because it does not interact with CYP 2D6 there is less risk of interactions with other drugs (81 -83).Mirtazepine (14)also shows little interaction with p450 cytochrome isozymes and there is only a low risk of drug interactions (84). Mirtazepine is a racemate, and the two enantiomers are eliminated at different rates, with a twofold higher rate of elimination of the (S)-enantiomer than of the (i )-enantiomer (84). 

The transport was blocked by selective 5-HT uptake inhibitors at low nanomolar concentrations whereas less selective or NE selective uptake inhibitors only blocked 5-HT at much higher concentrations. Dopamine and norepinephrine had virtually no effect on 5-HT uptake [1]. 

The S(+)isomer however is a 5-HT selective uptake inhibitor with a selectivity index of 31 amd a higher potency than both the racemate and the R(-)isomer in the... 

Basically 5-HT selective uptake inhibitors like MDL28618, femoxetine (fig. 5, table 6) and its dose structural analog paroxetine (table 6) can all be considered rigidified phenoxypropamine derivatives that may interact with the same recognition site at the 5-HT transporter. Fluoxetine and its rigidified analogs all seem to fit a common template (fig. 5). 

Cychc alcohols are excellent targets for enantioselective enzymatic acylations. For example, acylation of (65) with vinyl acetate catalyzed by Hpase SAM-II gives the (R),(3)-ester with 95% ee (81). Similarly (66), which is a precursor for seratonin uptake inhibitor, is resolved in a high yield and selectivity with Amano Hpase P (82). The prostaglandin synthon (67) is resolved by the same method into the optically pure alcohol in 35% yield (83). 

Two recently introduced antidepressants are notable m that they are selective serotonin uptake inhibitors Citalopram (19) is reported to be as effective as amitriptyline m the treatment of endogenous depression [75, 16] Fluoxetine (20) as the hydrochlonde is approved for major depressive disorders mcludmg those with concomitant anxiety Interestmgly, it also appears useful m the treatment of obesity [17]... 

Indeed, 5-HT is also a substrate for the 5-HT transporter, itself an important player in the treatment of depression, and more recently for the whole range of anxiety disorders spectrum (GAD, OCD, social and other phobias, panic and post-traumatic stress disorders). It is the target for SSRIs (selective serotonin reuptake inhibitors) such as fluoxetine, paroxetine, fluvoxamine, and citalopram or the more recent dual reuptake inhibitors (for 5-HT and noradrenaline, also known as SNRIs) such as venlafaxine. Currently, there are efforts to develop triple uptake inhibitors (5-HT, NE, and DA). Further combinations are possible, e.g. SB-649915, a combined 5-HTia, 5-HT1b, 5-HT1d inhibitor/selective serotonin reuptake inhibitor (SSRI), is investigated for the treatment of major depressive disorder. 

VMATs are not inhibited by drugs such as cocaine, tricyclic antidqnessants and selective serotonin reuptake inhibitors that affect plasma membrane monoamine transport. Amphetamines have relatively selective effects on monoaminergic cells due to selective uptake by plasma membrane monoamine transporters, but their effect appears to be mediated by their ability as weak bases to reduce ApH, the driving force for vesicular monoamine transport that leads to efflux of the vesicular contents into the cytoplasm. 

CCOHTA] Canadian Coordinating Office for Health Technology Assessment (1997). Selective Serotonin Re-uptake Inhibitors (SSRIs) for Major DepressionyVdJxll The Cost-... 

Donoghue JM (1998). Selective serotonin re-uptake inhibitor use in primary care a five year naturalistic study. Clin Drug Invest 16, 453-62. 

Sechter D, Lane RM (1997). Continuation therapy with selective serotonin re-uptake inhibitors./... 

CYP2C19 is another example of the existence of both cross-ethnic and inter-individual variations in drug metabolism. This enzyme is involved in the metabolism of many psychotropics such as diazepam and tertiary tricyclic antidepressants, as well as one of the selective serotonin re-uptake inhibitors (SSRIs), citalopram. Using S-mephenytoin as the probe, previous studies showed that up to 20% of East Asians (Chinese, Japanese, and Koreans) are PMs, when only 3-5%... 

What are the expected differences in side-effect profiles between ethnic groups, in particular with selective serotonic re-uptake inhibitors and atypical antipsychotics Can the morbidity of medication side effects be reduced, hence increasing treatment compliance and effectiveness ... 

Finley, P.R., Selective serotonin re-uptake inhibitors pharmacologic profiles and potential therapeutic distinctions, Ann. Pharmacother., 28(12), 1359-1369, 1994. 

Kunko P.M., Loeloff R.J., Izenwasser S. Chronic administration of the selective dopamine uptake inhibitor GBR 12,909, but not cocaine, produces marked decreases in dopamine transporter density. Naunyn Schmiedeberg s Arch. Pharmacol. 356 562, 1997. 

Collins S.L., Kunko P.M., Ladenheim B., Cadet J.L., Carroll F.I., Izenwasser S. Chronic cocaine increases kappa-opioid receptor density lack of effect by selective dopamine uptake inhibitors. Synapse. 45 153, 2002. 

Spealman R. Modification of behavioral effect of cocaine by selective serotonin and dopamine uptake inhibitors in squirrel monkeys. Psychopharmacology. 112 93, 1993. 

A major challenge to the development of new drugs is the discovery of new therapeutic targets. For example, the phenomenal success of fluoxetine (Prozac ) has been due to the fact that it was the first selective serotonin re-uptake inhibitor approved for world market release, combined with its improved adverse drug reaction profile. However, no new classes of antidepressants have emerged in recent years. 

The answer is d. (Kai ung, p 505.) Fluoxetine is a highly selective serotonin re uptake inhibitor (55RI) acting on the 5-1 IT transporter. It forms an active metabolite that is effective for several days. Selective serotonin reuptake inhibitors are inhibitors of cytochrome P450 isoenzymes, which is the basis of potential drug-drug interactions... 

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