Selectivity binding versus functional

Nicotine is highly selective for versus a, with respect to binding affinity (binding K = 1.05 r M versus 4 jM) and moderately selective with respect to functional activity (functional EC 4 [jM versus 54 jllM). Nicotine also binds with micromolaraffinity to muscle-type receptors, and affects activation in the mid to high micromolar range. Moreover, nicotine binds with micromolar affinity to ganglionic receptors and elicits functional responses in... 

The development status of these molecules is not known. It will be interesting to note whether any differences emerge from the CAAX competitive versus FPP competitive molecules as more data become available for these compounds. Since FPP itself contributes to the CAAX peptide binding pocket, the interaction of FPP competitive FTIs with CAAX peptide competitive FTIs will be of interest. The selectivity of FPP competitive FTIs for the FTase pathway versus other biochemical pathways utilizing FPP, such as ubiquinone synthesis and the heme farnesyltransferase, has also not been reported. These other FPP reactions have important roles in mitochondrial function, which presents some risk for adverse events or possibly opportimities for modulating early apoptotic events. 

The TCAs resemble the SNRIs in function, and their antidepressant activity is thought to relate primarily to their inhibition of 5-HT and norepinephrine reuptake. Within the TCAs, there is considerable variability in affinity for SERT versus NET. For example, clomipramine has relatively very little affinity for NET but potently binds SERT. This selectivity for the serotonin transporter contributes to clomipramine s known benefits in the treatment of OCD. On the other hand, the secondary amine TCAs, desipramine and nortriptyline, are relatively more selective for NET. Although the tertiary amine TCA imipramine has more serotonin effects initially, its metabolite, desipramine, then balances this effect with more NET inhibition. 

As can be seen in Table 2.17, increasingthe R group size from H to Me to Phe top-tBuPhe (Ia,Ib, Ic, and Id, respectively )led to a steady increase in binding affinity for the 6-opioid receptor from about 6 fjM to about 8 nAf as predicted (242). Most important, the selectivity for the 8-opioid receptor versus the /a-opi-oid receptor also increased very substantially from nonselective to over 2000-fold selective (Table2.17), which actually is somewhat more selective than DPDPE or [(2S,3i )TMT ] DPDPE (see Table 2.16 for comparison). In the functional assays that make use of the classical guinea pig ileum (GPI, for the /i-re-ceptor) and mouse vas deference (MVD, for... 

Danishefsky s synthesis (Scheme 4) [7] started from the readily available Wieland-Mie-scher ketone (19) which, by a series of mainly protection and oxidation reactions, was transformed to the fully functionalized C ring precursor 21. The oxetane moiety was introduced very early on in the synthesis, from a corresponding triol, again by nucleophilic substitution at C5. Noteworthy is the selective protection or modification of primary versus secondary versus tertiary hydroxy groups for this purpose. The benzyl protected enolized form 20 then could be oxidized, cleaved oxidatively and processed to compound 21 which, apart from complete C/D rings, possesses the necessary handles (C2 and C9/10) to bind to the A ring precursor 22 and thus form the B ring. 

In a related example, MIPs toward l-(l-naphthyl) ethylamine (12) also showed enantioselectivity. In fact, the separation factor was larger than in the case of oc-methylbenzylamine (Table 5). The binding affinities of these two primary amine functionalized templates are roughly the same. However, the separation factor for I-(1-naphthyl) ethylamine is greater than that for a-methylbenzylamine. Therefore, the selectivity enhancement of the l-(l-naphthyl) ethylamine vs. a-methylbenzylamine must be due to the size difference of the naphthyl group versus the phenyl group. From this finding comes rule 7 ... 

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