Thalidomide and its immunomodulatory imide drugs (IMiDs) analogues CC-5013 (Revlimid, Lenalidomide) and CC-4047 (Actimid, Pomalidomide) have been used as anti-inflammatory and anticancerous drugs in the recent years. Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor-alpha (TNF-alpha), interleukins (IL) 1-beta, 6, 12, and granulocyte macrophage-colony stimulating factor (GM-CSF). They also costimulate primary human T, NKT and NK lymphocytes inducing their proliferation, cytokine production, and cytotoxic activity. On the other hand, the compounds are anti-angiogenic, anti-proliferative, and pro-apoptotic. Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment. In this review, we explore the current trend of the different structures, the new patents, and the possible new applications in different pathologies.

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Trimetoquinol [1-(3',4',5'-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4- tetrahydroisoquinoline , TMQ] exists as two enantiomers, and the (-)-(S)-isomer is a potent beta-adrenergic receptor (beta-AR) agonist. Experiments were conducted to examine the functional and biochemical potencies of the (S)-and (R)-enantiomers of TMQ for interaction with beta-AR subtypes in tissues, membrane fractions, and cell systems. The isomeric-activity ratios (IARs) of the TMQ isomers [(S)-isomer > > (R)-isomer] for stimulation of beta 1- and beta 2-AR of guinea pig right atria and trachea were 224 and 1585, respectively; these IARs were similar to those observed on atypical beta-AR systems of rat distal colon (575), rat brown adipocytes (398), but differed from that of rat esophageal smooth muscle (2884) in the presence of pindolol. In the absence of pindolol, the potencies for the TMQ enantiomers were slightly increased; however, the IARs remained unchanged in rat distal colon, rat brown adipocytes, and rat esophageal smooth muscle. Similarly, radioligand binding studies demonstrated that the TMQ isomer beta-AR affinities were stereoselective for the (-)-(S)-isomer in membranes of guinea pig left ventricle (beta 1) and lung (beta 2) giving IARs of 115 and 389, respectively; and in E. coli expressing human beta 1- and beta 2-AR giving IARs of 661 and 724, respectively. Corresponding IARs of receptor affinities and stimulation of cAMP accumulation in Chinese hamster ovary cells expressing human beta 2-AR and rat beta 3-AR were 331 and 282, and 118 and 4678, respectively. These results indicate that the (-)-(S)-isomer of TMQ exhibits high affinity, and is a potent and highly stereoselective agonist for each beta-AR subtype, that the isomers generally fail to differentiate between the beta-AR subtypes, and that, based upon differences in IAR within beta 3-AR containing systems, subtypes of atypical beta (or beta 3)-AR may exist in adipose tissue and smooth muscle.

1 Several imidazolines were examined for the antagonism of muscarinic (M3) and other receptors on the isolated ileum of guinea-pig. The effect of the muscarinic agonist, carbachol was competitively antagonized by oxymetazoline at 10(-5) m. A dissociation constant (KB) of 3.6 microm for the antagonist was calculated. At higher concentrations, 3 x 10(-5) and 10(-4) m, of the antagonist, the agonist dose-response curve was shifted to the right with a decrease in the maximum effect. Thus, a non-competitive block occurred at higher concentrations of oxymetazoline. Blockade of histamine H, and serotonin receptor-mediated responses by oxymetazoline were also of a non-competitive type. 2 Naphazoline at 10(-4) m shifted the dose-response curves of carbachol and serotonin to the right by two- and 15-fold, respectively. The maximum contraction of the agonist was not affected. Tolazoline also had a weak antihistaminic activity. At similar concentration; tetrahydrozoline clonidine and phentolamine at 10(-5) m produced two-, three- and four-fold shift of the carbachol dose-response curve without significant changes in the maxima. Neither methoxamine, p-amino-clonidine nor cimetidine blocked the responses of carbachol. 3 The isosteric nature of the alpha-adrenoceptor agonist, oxymetazoline and some imidazolines with carbachol, in part, explains its molecular competition at the muscarinic M3 receptor of the guinea-pig ileum. Surprisingly, contractile effects of carbachol (M3), histamine (H1) or serotonin (5HT3/5HT4) were not influenced by methoxamine, tetrahydrozoline, p-amino clonidine and cimetidine.