PLAN ESTRATÉGICOPARA ARH EN LA EMPRESA PROVEEDORA DEL ORIENTE

8.1

Figure 8.2 Cross-eyed stereo overlay of compounds 8.4a (blue) and 8.4b (green) docked in within the putative binding site of a homology model of the 5HT

Perhaps more compelling, the conformationally-restricted phenethylamines on which stereoisomer was tested, meaning they

activation of several downstream signaling pathways: phospholipase C triphosphate turnover compared to arachidonic acid and

arachidonyl glycerol.6 _{Most data regarding ligand interactio}

comes from phospholipase C (PLC)

selectivity is an emerging concept in pharmacology and

154

. Aminobenzocyclobutene analogs of 2C-B

8.4a 8.4b

eyed stereo overlay of compounds 8.4a (blue) and 8.4b (green) docked in within the

putative binding site of a homology model of the 5HT2A receptor.4,5

Perhaps more compelling, the experimental efficacy data suggested that these restricted phenethylamines expressed functional selectivity depending on which stereoisomer was tested, meaning they were able to differentially stimulate the activation of several downstream signaling pathways: phospholipase C-mediated inosit triphosphate turnover compared to arachidonic acid and production of endocannabinoid

Most data regarding ligand interaction with serotonergic systems comes from phospholipase C (PLC)-mediated responses. The concept of functional selectivity is an emerging concept in pharmacology and research suggests that subtle

eyed stereo overlay of compounds 8.4a (blue) and 8.4b (green) docked in within the

suggested that these expressed functional selectivity depending were able to differentially stimulate the mediated inositol production of endocannabinoid 2-

n with serotonergic systems The concept of functional research suggests that subtle

155

changes in ligand structure results in the activation of a multitude of downstream signaling pathways.6,7 _{Further, these subtle variations in ligand structure have significant impacts on}

overall in vivo activity of the drugs.8 _{Our understanding of the connection between the}

ligand/receptor interaction and in vivo activity is not well established.

In light of the interesting results presented above, the research described in this chapter was set in motion with the ultimate goal of exploring the synthesis and pharmacology for ABCB analogs of the other two general classes of PEAs, the stimulants and entactogens, represented by prototypical compounds 8.2 and 8.3, respectively. We envisage that these compounds could help verify several hypotheses. In the same way that optimal binding is achieved in 5HT2A receptor when the protonated ethylamine side chains

of PEAs are held outside of the plane of the aromatic ring, ABCB analogs of prototypical stimulants and entactogens 8.2 and 8.3 would demonstrate that the optimal binding orientation prefers similar placement of the protonated amine at the active sites of other targets within the CNS including, but not limited to dopamine, serotonin and norepinephrine receptors and/or transporters. In support of this hypothesis, a recent study of the stimulant 8.2 docked at the binding site of the dopamine transporter appears to demonstrate this preferred out-of-plane conformation (Figure 8.4).9 _{Second, the rigid}

ABCB analogs would exhibit greater functional selectivity at receptor sites compared to their flexible parent compounds. Given that the binding of rigid compounds could bias receptor towards fewer conformational microstates, it is possible that the rigid compounds would differentially affect second messenger pathways for a single receptor compared to the flexible analog. 10

Figure 8.3. Amphetamine, 8.2, (green) docked within th

Rigid ABCB analogs of PEAs

understanding of multiple receptor pharmaco

scientists in a number of fields including: computational chemists studying homology models of the receptor

signaling cascade involved in GPCR

comparing the crystal structures of rigid and flexible analogs, synthetic organic chemists interested in benzocyclobutane synthesis, and medicinal chemists developing medications for treating psychological disorde

With the above rationale and hypotheses in mind, we set forth to develop a robust synthetic methodology capable of producing the ABCB analogs of PEAs

readily available inexpensive starting materials.

156

. Amphetamine, 8.2, (green) docked within the binding site of the dopamine transporter

PEAs will provide important probes capable of furthering our receptor pharmacophores. These compounds will be useful to scientists in a number of fields including: computational chemists studying

receptors, molecular biologists interested in the molecular signaling cascade involved in GPCR-mediated neurotransmission, x-ray crystallographers comparing the crystal structures of rigid and flexible analogs, synthetic organic chemists interested in benzocyclobutane synthesis, and medicinal chemists developing medications for treating psychological disorders.

With the above rationale and hypotheses in mind, we set forth to develop a robust synthetic methodology capable of producing the ABCB analogs of PEAs 8.2

readily available inexpensive starting materials.

e binding site of the dopamine transporter9

will provide important probes capable of furthering our . These compounds will be useful to scientists in a number of fields including: computational chemists studying in silico

, molecular biologists interested in the molecular ray crystallographers comparing the crystal structures of rigid and flexible analogs, synthetic organic chemists interested in benzocyclobutane synthesis, and medicinal chemists developing medications

With the above rationale and hypotheses in mind, we set forth to develop a robust 8.2 and 8.3 from

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8.3

Results and Discussion

Retrosynthetic analysis of the target scaffolds illustrated in Scheme 8.3 indicated that 1-cyanobenzocyclobutene derivatives 8.5a and 8.5b could potentially be key intermediates. Using a parallel synthetic approach, virtually any ABCB PEA analog, including the target compounds 8.15a and 8.16, could potentially be synthesized from derivatives of this versatile substrate. ABCBs bearing alpha-methyl functionality, as in 8.15a,b, could be produced by a Grignard mediated process from 8.5a,b followed by direct reduction of the intermediate imine to the corresponding amine. Alternatively, hydrolysis of the intermediate imine would afford ketone 8.6, precursor to target compound 8.16, which could undergo reductive amination with the appropriate (alkyl)amine. A second approach to 8.16 could involve reductive amination on 8.15b using an appropriate carbonyl compound.