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A recently reported study on the azidolysis of vinyl epoxides is extended to analogous N-protected aziridines (I) to produce azides (II), accompanied by low amounts of azides (III).

The synthesis of a series of 9-methyladenines bearing bulky groups at the 8-position and evaluations of their affinity for the four human adenosine receptor subtypes are presented.

Neuropeptide S (NPS) is a 20-amino acid peptide of great interest due to its possible involvement in several biological processes, including food intake, locomotion, wakefulness, arousal, and anxiety. Structure-activity relationship studies of NPS have identified key points for structural modifications with the goal of modulating NPS receptor (NPSR) agonist activity or achieving antagonism at the same receptor. Only limited information is available for nonpeptide NPSR antagonists. In the last year, several studies have been reported in literature which present various series of small molecules as antagonists of this receptor. The results allow a comparison of the structures and activities of these molecules, leading to the design of new ligands with increased potency and improved pharmacological and pharmacokinetic profiles. This work presents a brief overview of the available information regarding structural features and pharmacological characterization of published nonpeptide NPSR antagonists.

We report the resolution of racemic (+/-)-1 with (R)-(+)-methylbenzyl isocianate and the synthesis of (R)-1 and (S)-1 via Sharpless chiral epoxidation. The enantio- and tissue-selectivity of such enantiomers, as beta- and alpha-adrenoceptor antagonists, were studied. Compound 1, while confirming the potent beta-blocking activity, displayed a modest enantio-selectivity towards beta 1- and beta 2-adrenoceptors. All the compounds displayed no activity as alpha-adrenoceptor blockers.

The synthesis of a series of piperazinyl-pyridazinones is reported. The blocking activity of these compounds was determined on the pre- and postsynaptic α-adrenoreceptors of isolated rat vas deferens. For compounds 7, 17 and 18, the hypotensive activity was also evaluated.

In order to develop compounds which may be useful in the treatment of memory and cognitive disorders we have synthesized and tested some 1,3-oxathiolane derivatives bearing an amidine function instead of the classical ammonium head, with the aim of improving brain penetration. The compounds were tested on peripheral and central models of muscarinic receptors. The results show that, unlike for other series of muscarinic ligands, this modification results in the reduced potency of antagonists, shifts the activity of agonists toward weak antagonism and does not introduce any noteworthy subtype selectivity.

Summary The synthesis of selected 4-[4-(phenoxyethyl)-1-piperazinyl]-3(2 H )-pyridazinones and alkane-bridged dimers of 4-, 5- and 6-[4-(phenoxyethyl)-1-piperazinyl]-3(2 H )-pyridazinones is reported. The blocking activity of these compounds was determined on the pre- and postsynaptic α-adrenoreceptors of isolated rat vas deferons.

Tetraamine disulfides 1–10 were designed by combining the structural features of benextramine, an irreversibleα1/ga2 adrenoceptor antagonist, and prazosin, a selective competitive α1-antagonist. Their biological profile was assessed by functional and binding assays. In rat vas deferens functional experiments, tetraamine disulfides 1–10 displayed a marked selectivity at α1-adrenoceptors. Furthermore, they acted as competitive antagonists at α1-adrenoceptors and weak noncompetitive (irreversible) antagonists at α2-adrenoceptors. In binding assays, performed at α1-adrenoceptors of rat liver (α1B) and submaxillary gland (α1A), compound 5 showed an 11-fold selectivity for α1B-adrenoceptors in contrast to both prazosin and benextramine, which were not selective or selective for the α1A-subtype respectively.

The four homochiral 4-deoxy-4,4-difluoromuscarine stereoisomers (difluoromuscarines) were prepared in very high enantiomeric excess. A convenient sequence based on the use of natural as well as “un...

4-(4-Fluorobenzoyl)-1-[2-(4-iodo-2,5-dimethoxyphenyl)ethyl]piperidine ( 7 ) and its derivatives modified at the carbonyl group of the fluorobenzoyl moiety were prepared and evaluated for affinity at 5-HT 2A , 5-HT 2C (rat cortex) and 5-HT 2B (rat stomach fundus) serotonin receptors. Compound 7 bound the 5-HT 2A sites with higher affinity (K i = 8.2 nM) than the 5-HT 2B (K b = 1 290 nM) and 5-HT 2C ones (K i = 54.2 nM). Modification of the benzoyl carbonyl group decreased the 5-HT 2A and 5-HT 2C affinities but did not significantly influence 5-HT 2B affinity. This suggests that the carbonyl group is the determinant for the interaction with 5-HT 2A and 5-HT 2C receptor subtypes. Compound 7 was found to be a 5-HT 2A receptor antagonist.

A series of beta-chloroethylamines 5--18, structurally related to the irreversible alpha(1)-adrenoceptor antagonist phenoxybenzamine [PB, N-benzyl-N-(2-chloroethyl)-N-(1-methyl-2-phenoxyethyl)amine hydrochloride, 1] and the competitive antagonist WB4101 [N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-N-[2-(2,6-dimethoxyphenoxy)ethyl]amine hydrochloride, 2], were synthesized and evaluated for their activity at alpha-adrenoceptors of the epididymal and the prostatic portion of young CD rat vas deferens. All compounds displayed irreversible antagonist activity. Most of them showed similar antagonism at both alpha(1)- and alpha(2)-adrenoceptors, whereas compounds 13 and 18, lacking substituents on both the phenoxy group and the oxyamino carbon chain, displayed a moderate alpha(1)-adrenoceptor selectivity (10--35 times), which was comparable to that of PB. Compounds 14 and 15, belonging to the benzyl series and bearing, respectively, a 2-ethoxyphenoxy and a 2-i-propoxyphenoxy moiety, were the most potent alpha(1)-adrenoceptor antagonists with an affinity value similar to that of PB (pIC(50) values of 7.17 and 7.06 versus 7.27). Interestingly, several compounds were able to distinguish two alpha(1)-adrenoceptor subtypes in the epididymal tissue, as revealed by the discontinuity of their inhibition curves. A mean ratio of 24:76 for these alpha(1)-adrenoceptors was determined from compounds 8--10, 12, and 15--17. Furthermore, compounds 9, 10, 12, 16a, and 16b showed higher affinity towards the minor population of receptors, whereas compounds 8, 15, and 17 preferentially inhibited the major population of alpha(1)-adrenoceptors. In addition, selected pharmacological experiments demonstrated the complementary antagonism of the two series of compounds and their different, preferential affinity for one of the two alpha(1)-adrenoceptor subtypes. In conclusion, we found beta-chloroethylamines that demonstrate a multiplicity of alpha(1)-adrenoceptors in the epididymal portion of young CD rat vas deferens and, as a consequence, they are possible useful tools for alpha(1)-adrenoceptor characterization.

Novel derivatives of natural muscarine and allo -muscarine, i.e. the benzyl ethers (−)- 10 and (−)- 12 and the benzoate (−)- 13 , were synthesized in very high enantiomeric excess. Target compounds were tested in vitro on guinea pig tissues, and their muscarinic potency was evaluated at M 2 (heart force and rate) and M 3 (ileum and bladder) receptor subtypes. The derivatives under study were also assayed in vivo on pithed rat. In addition, muscarinic receptor heterogeneity was investigated by determining the affinity and the relative efficacy of compounds (−)- 10 , (−)- 12 and (−)- 13 at M 2 (heart force and rate) and M 3 (ileum and bladder) receptor subtypes.