MATERIALES Y MÉTODOS 3.1 Lugar de estudio
3.5 Materiales y equipos 1 Material de campo
3.6.1 Etapa pre experimental
3.6.2.7 Determinación de la producción de metano
In an attempt to develop aryloxyalkylamines analogues of propranolol as selective 5 -H T ia agents, Pierson et described the first 5 -H T ia structu re-activity relationship analysis of this series of compounds. The features contributing to the adrenergic affinity of aryloxypropanolamines were thought to include the following:
• a four-atom chain between the aromatic unit and the terminal amine • a secondary terminal amine
• bulky or branched amine substituents • a hydroxyl group on the side chain
Introduction
A series of aryloxyalkylamines was synthesised to ascertain which of the above factors contribute to the 5-HT-ia or 5-HT-ib affinity of these compounds. The results are summarised in Table 1.6.
A r - X - ( C H 2 ) n - N R l R 2 Compound Ar X n r2 Kj/nM 5-H T1A 5-HT 1B
P
7 2 Ph NH 3 Me Me > 2 5 0 0 0 >104 - 7 3 Ph 0 3 Me Me 4 8 5 0 >104 - 7 4 Ph 0 3 npr npr 2 7 5 0 >104 - 7 5 Naph 0 3 Me Me 345 1000 2 4 0 0 7 6 Naph 0 3 npr npr 4 50 6 1 0 0 - 7 7 * Naph 0 3 (OH) npr npr 1325 8 0 0 0 - 7 8 Naph 0 4 Me Me 4 00 1 000 - 7 9 Naph 0 2 Me Me 80 1 500 4 5 0 08 0 Naph 0 3 "Bu "Bu 225 5 6 5 0 8 3 0 0 8 1 Naph 0 2 "Bu "Bu 150 9 0 0 0 >104
8 2 Naph 0 2 Me npr 45 1800 5 3 0 0
8 3 Naph 0 2 Et "Bu 39 1 100 5 0 0 0
8 4 Naph 0 2 H H 60 - -
8 5 Naph CH2 2 Et "Bu 3 00 - -
‘ Compound contains a 2-OH group in the side chain
Table 1.6
1.8.3.1 Aryl Group
A comparison of the phenyloxyalkylamines 73 and 74 with their naphthyloxyalkylamine analogues 75 and 76, demonstrates that those possessing the naphthalene ring system appear to exhibit greater potencies at the 5 -H T ia receptor. In this series of aryloxyalkylamines, only a limited investigation into phenyl ring substitution was carried out. Substitution of the 2-position of the phenyl ring of compound 73 with either a OH or OMe, did not significantly affect 5-HT-|a or 5- HT-ib affinity. Substitution of the naphthalene ring was not investigated in this study.
Introduction
1.8.3.2 Arom atic Linkage
In the limited number of examples described, such as compounds 72 and 73 in the phenyl series, it can be seen that replacement of the ether linkage by -NH is detrimental to affinity at 5- H T ia receptors. In the naphthalene series, replacement of the ether linkage of compound 83 by a methylene unit (compound 85) is also detrimental to the affinity at 5 -H T ia receptors.
1.8.3.3 Alkyl Side Chain
In the naphthalene series of derivatives (compounds 75, 78 and 79), the optimum iength of the alkyl chain appears to be ethyl, which is at least four times more potent than the analogous compounds containing either a propyl or butyl side chain, the latter two showing little difference in 5-HT-IA receptor affinity. Compound 79, which contains an ethyl chain, in addition to being the most potent at 5-H Ti a receptors, is also the most selective.
1.8.3.4 Hydroxyl Group
Since the hydroxyl group of aryloxyalkylamines is required for p-adrenergic receptor activity, the question arises as to whether this group contributes to their 5-H Ti a receptor affinity. Compound 76, an analogue of compound 77 that lacks the hydroxyl group in the side chain, is three times more potent. A comparison of these two compounds also reveals that the 5-H T i b affinity is slightly decreased in the non-hydroxylated side chain analogue. Unfortunately p-adrenergic receptor binding data were not reported for these two compounds.
1.8.3.5 Term inal Amine Substituents
In the naphthalene series possessing an ethyl side chain (compounds 79, 81, 82, 83 and 84),
the 5-H TiA receptor affinity decreases in the following order: = Et, Bu > Me, Pr > H, H > Me, Me > Bu, Bu, although the differences are marginal (2- to 4-fold). It therefore appears that the amine alkyl substituents do not play a significant role in the 5-HT-|a receptor binding of these compounds. This is also reflected in the series of compounds that possess a propyl side chain (compounds 75, 76 and 80). As a result of this structu re-activity analysis, two potent 5 -H T ia receptor agents, 82 and 83, have been identified. These compounds display over 100-fold selectivity for 5 -H T ia receptors versus p-adrenergic receptors and are 20- to 40-fold less potent at 5-HT 1B receptors.
Introduction
As mentioned earlier, Pierson’s study was the earliest attempt to correlate the structure of aryloxyalkylamines with their 5-H Ti a affinity. Selectivity data for a limited number of compounds were given in this study, although functional data for the compounds were not reported. The latter point is of particular interest since one of the main reasons for the interest in this class of (3- adrenergic receptor ligands is their antagonist properties at the 5-H Ti a receptor. It would therefore be interesting to investigate whether these compounds retain the antagonist activity of the lead compounds.
1.8.3.6 Summary of BAR for Naphthalene Derivatives
In summary, for enhanced 5 -H T ia affinity and selectivity in this series of propranolol derivatives, the following factors appear to be important (Figure 1.7):
• An ethyl side chain without a hydroxyl group
• A tertiary terminal amine, with Et, Bu and Me, Pr substitutions being optimal
O H
Increase 5-HTia affinity and selectivity
Remove OH group Shorten side chain
Tertiary amine
NR^R2
Figure 1.7
1.8.3.7 Naphthalene Substitution
As discussed previously, the 2-substituted derivatives of pindolol, i.e. cyanopindolol and SDZ 21009 (Table 1.3) are more potent 5 -H T ia and 5-HT-|b receptor ligands than pindolol itself. Therefore the substituent must provide a further point of interaction at the 5-H T sites, although the nature of this putative interaction is unclear, since data exists only for a limited number of substituents, i.e., CN, CONH2 and CO2R. The question arises as to whether substituents on the naphthalene ring of propranolol analogues might also increase their affinity for 5-HT receptors. By simple alignment of the structures (Figure 1.8), it can be seen that the 6- and 7-positions of the naphthalene ring of propranolol might correspond to the 2-position of the indole ring:
Introduction
Figure 1.8
In an attem pt to investigate the structure-activity relationships of substituted propranolol analogues, and to develop them as potential 5-H T i g receptor agents, Gharagozloo^ synthesised a series of 1,6-substituted naphthyloxypropanolamines and naphthyloxyalkylamines with the following general structure:
1 d2
N R 'R
C O R '
X = H, OH
However the compounds in this series were found to be either inactive or possessed weak (micromolar) affinities for both 5 -H T ia and 5 -H T ib receptors, and therefore represented no improvement either on propranolol or on the propranolol analogues synthesised by Pierson et ai.
Selection of Compounds