Piripitsi, Antonia; (1996) Synthesis and structure-activity studies of novel compounds acting at histamine H₃ receptors. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The histamine H3 receptor is regarded as an important general regulatory mechanism, which affects a variety of brain functions, but also influences various physiological processes in peripheral tissues. In view of these considerations, the H3 receptor has been the target for a successful development of selective H3 agonists and antagonists. This thesis describes different approaches for the design and synthesis of potential H3 ligands (both agonists and antagonists), which have been used for a structure-activity exploration in order to find new leads for the development of highly potent, selective, brain penetrating and non-toxic H3 ligands for investigative clinical use in humans. Starting from imetit (I, n=2, R1=R2=H), one of the most potent and selective H3 agonists synthesised so far, in an attempt to reduce the H-donor capability of this molecule and hence improve brain penetration, the N-H of the isothiourea moiety was replaced by N- alkyl. This molecular modification led from agonism (I, n=2, R 1=MR,R2=H) through partial agonism (I, n=2, R 1=Et,R2=H ) to antagonism (I, n=2, R1 = Pr,R2=H). Alkyl groups, one on each nitrogen atom of the isothiourea moiety of imetit, had been shown to enhance antagonist activity up to an optimum in which R1=R2=Bu (Ki =5.4 x 10-9 M). Higher homologues of dibutyl imetit were then synthesised (I, n=3, 4, R1=R2=Bu) and it was found that the propylene chain is optimal in length for H3 antagonist activity for this type of analogue (Ki=1.5 x 10 -9 M). Replacement of the imidazole moiety of this propylene analogue with 2-pyridyl led to a large drop in antagonist activity, suggesting that the imidazole ring is an important structural feature for H3 antagonists. For a series of phenoxypropylimidazoles (II, n=3), substitution at the 4-position exclusively gives H3 antagonists, whereas the 3-position is critical for H3 agonism. In the case of H3 antagonists, for analogues of this general type where n=3 and R=4 COME, 4-CPEt and, their corresponding butyl homologues (II, n=4) were found to be much less active. In the case of H3 agonism, for the the 3-CF3 and 3-COEt substituted propyl compounds (II, n=3, a full and a partial agonist in vivo respectively), their butyl homologues were still partial agonists, though slightly less potent. Nevertheless, whereas the 3-COEt and the 3-CH(CH 3)2-substituted propyl analogues (II, n=3) had been both found to be partial agonists in vivo, the butyl homologue of the former was not active in vivo and in the case of the latter its butyl homologue was a potent H3 antagonist. Taking all these findings together, it seems that for analogues of the general type II, the propylene chain is optimal in length for both H3 agonist and H3 antagonist activity. For the 3-CF3 substituted propyl compound (II, n=3) which was the only analogue of this series found to act as a full agonist in vivo, branching the propylene side chain led to a dramatic loss of the in vivo activity. For a series of non-imidazoles, using compound III (R=H, X=CH2, n=3, Rl=H, R2=Et) as a lead, the possibility of optimising the H3 antagonist activity was investigated using different approaches. Introduction of several substituents (R=OCH3, NO2, Cl, F, NH2), spanning a variety of different properties on the phenyl ring of the above mentioned lead compound did not improve activity. However by inserting O or S, replacing NH with NEt and by varying the alkyl chain length (n = 3-6), an H3 antagonist with relatively good in vivo activity was obtained (III, R=H X=O, n=5, R1=R 2=Et). Further improvement was sought by varying the size of the dialkyl substituent on the terminal nitrogen atom of this diethyl analogue (III, X=O, n=5, R1=R2=Me, Pr, Bu). Surprisingly this led from antagonism (III, X=O, n=5, Rl=R2=Me) to agonism (III, X=0, n=5, R1=R2=Bu).

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