[Studying spasmolytic activity of imidazo[1,2-a]azepinium derivatives on isolated strips of rat bladder].

We have performed screening tests for imidazo[1,2-a]azepine derivatives by studying their antispasmodic activity on the isolated strips of urinary bladder of female rats. Test compounds showed the ability to reduce the basal tone of bladder stripes on the background of hyperpotassium constriction (40 mM KCl).

Synthesis and preliminary ex vivo evaluation of the spasmolytic activity of 1,3-thiazolium- and 1,3,4-thiadiazolium-5-methylthio- and 5-thioacetate derivatives.

Seven new compounds have been synthetized in satisfactory yields (51-78 %) through the treatment of mesoionic 1,3-thiazolium-5-thiolate (4a-d) and 1,3,4-thiadiazolium- 5-thiolate (10a,b) with chloroacetic acid or methyl iodide: 1,3,4-thiadiazolium-5-methylthio- (11) and 5-thioacetate (12). The structure of the title compounds was elucidated by elemental analysis, IR, (1)H and (13)C NMR spectroscopy. The newly synthesized compounds 5a, 6a, 11 and 12 were evaluated for their ex vivo spasmolytic potential on four isolated smooth muscles (rat aorta and uterus, guinea pig ileum and trachea) and compared with scopolamine. Some of the compounds exhibited potent spasmolytic activity equal to or stronger than scopolamine.

Microwave-assisted synthesis and spasmolytic activity of 4-indolylhexahydroquinoline derivatives.

In the present study a microwave-assisted one-pot method was applied for the synthesis of 18 novel condensed 1,4-dihydropyridines carrying the indole moiety. The compounds were achieved by the reaction of appropriate 1,3-cyclohexanedione, substituted indole carboxaldehyde derivative, alkyl acetoacetate and ammonium acetate in methanol, according to a modified Hantzsch reaction. The structure elucidation of the compounds was carried out by spectral methods including X-ray studies. Their spasmolytic activities through calcium channel blockade were assayed on isolated rat ileum. The obtained results indicated that the introduction of the brom atom on the indole ring altered the mentioned activity positively.

Investigation of the extraction process and phytochemical composition of preparations of Dodonaea viscosa (L.) Jacq.

ETHNOPHARMACOLOGICAL RELEVANCE: Oily substances extracted by a crude process from the stem including its bark (hereafter referred to as the stem) of Dodonaea viscosa (L.) Jacq. has been used by practitioners of traditional Indian medicine to treat inflammation, pain and other musculoskeletal disorders. AIM OF THE STUDY: The aim of this study is to understand the scientific phenomena behind the process adopted by traditional practitioners for extraction and to establish the principle of extraction process by a simulated scientific method. The study also investigates the phyto-chemical composition of the extracts and compares the simulated extract with the traditional extract. MATERIALS AND METHODS: The traditional method was subjected to a detailed analysis, and it was identified as a crude equivalent of pyrolysis. The process was simulated under controlled conditions in a self-fabricated prototype pyrolyser. The extracts from both methods were compared for their compositional identity and phytochemistry using FT-IR and GC-MS. RESULTS: The results show that in both the cases, the presence of dihydroxy, dimethyl and other substituted catechols, which are postulated as pyrolysate derivatives of the anti-spasmodic flavonoids quercetin, rutin, kaempferol and sakuranetin. CONCLUSION: The applied principle of extraction is identified as slow pyrolysis, which is supported by the visual and chemical similarities of the extracts from both methods. The phyto-chemical analysis indicates the presence of anti-spasmodic chemicals in the extract from the stem of Dodonaea viscosa (L.) Jacq.; these chemicals are likely the active substances in the treatment of inflammation, pain and other musculoskeletal disorders, and the research substantiates the stem's historical use by traditional practitioners.

Synthesis, biological evaluation, and docking studies of gigantol analogs as calmodulin inhibitors.

Several analogs of gigantol (1) were synthesized to evaluate their effect on the complexes Ca(2+)-calmodulin (CaM) and Ca(2+)-CaM-CaM sensitive phosphodiesterase 1 (PDE1). The compounds belong to four structural groups including, 1,2-diphenylethanes (2-11), diphenylmethanes (13-15), 1,3-diphenylpropenones (16-18), and 1,3-diphenylpropanes (20-22). In vitro enzymatic studies showed that all compounds except 11 inhibited the complex Ca(2+)-CaM-PDE1 with IC(50) values ranging from 9 to 146 µM. On the other hand, all analogs but 11, 12 and 15 quenched the extrinsic fluorescence of the CaM biosensor hCaM-M124C-mBBr to different extent, then revealing different affinities to CaM; their affinity constants (K(m)) values were in the range of 3-80 µM. Molecular modeling studies indicated that all these compounds bound to CaM at the same site that the classical inhibitors trifluoperazine (TFP) and chlorpromazine (CPZ). Some of these analogs could be worthy candidates for developing new anti-tumor, local anesthetics, antidepressants, antipsychotic, or smooth muscle relaxant drugs, with anti-CaM properties due to their good affinity to CaM and the straightforwardness of their synthesis. In addition they could be valuable tools for the study of Ca(2+)-CaM functions.

Synthesis, spasmolytic activity and structure-activity relationship study of a series of polypharmacological thiobenzanilides.

Recently we presented a series of benzanilide derivatives with a selective spasmolytic effect on terminal ileum preparations of the guinea pig. In this report we demonstrate a further development of these compounds. The exchange of the amide oxygen against a sulfur atom resulted in an up to 325 fold increase of the antispasmodic activity of the thiobenzanilide (IC(50) of 0.1 µM) compared to its benzanilide derivative. Considering their mode of action the compounds interacted with several molecular targets, suggesting that we identified a chemical identity able to modulate multiple targets simultaneously. Furthermore, based on this data set, we present a structure-activity relationship study supporting the important role of the sulfur atom.

A concise, biomimetic total synthesis of (+)-davanone.

A concise, biomimetic synthesis of the antifungal and antispasmodic natural product (+)-davanone is described. The key stereoselective reactions are a Sharpless asymmetric epoxidation, a thiazolium-catalyzed esterification, and a palladium-mediated cyclization. All carbons are derived from isoprene units and no protecting groups are used, permitting an atom- and redox-economical synthesis.

Synthesis and adrenolytic activity of 1-(1H-indol-4-yloxy)-3-{[2-(2-methoxyphenoxy)ethyl]amino}propan-2-ol and its enantiomers. Part 1.

The synthesis of (2RS)-1-(1H-indol-4-yloxy)-3-{[2-(2-methoxyphenoxy)ethyl]amino}propan-2-ol ((RS)-9) and its enantiomers has been described and tested for electrocardiographic, antiarrhythmic, hypotensive and spasmolytic activities as well as for alpha(1)-, alpha(2)- and beta(1)-adrenoceptors' binding affinities. All compounds significantly decrease systolic and diastolic blood pressure, and possess antiarrhythmic activity and affinity to alpha(1)-, alpha(2)- and beta(1)-adrenoceptors. The results suggest that the antiarrhythmic and hypotensive effects of these compounds are related to their adrenolytic but not spasmolytic properties.

Hyoscine butylbromide - a review on its parenteral use in acute abdominal spasm and as an aid in abdominal diagnostic and therapeutic procedures.

BACKGROUND: Being a quaternary ammonium compound derived from scopolamine, the alkaloid hyoscine butylbromide (HBB) exerts anticholinergic effects without side effects related to the central nervous system because it does not pass the blood-brain barrier. Clinical experience with this antispasmodic dates back to the 1950s and led to its registration for treating abdominal cramps/spasm and for diagnostic imaging purposes. OBJECTIVES AND SCOPE: This review focuses on the therapeutic efficacy and safety of the parenteral administration of HBB for treating biliary and renal colic and acute spasm in the genito-urinary tract. In addition, its value for diagnostic or therapeutic procedures in the abdomen, as well as for labour and palliative care, is reviewed. With the generic and trade name of the drug combined with various search terms related to the relevant clinical applications, a thorough literature search was performed in the Medline and EMBASE databases in April 2008. FINDINGS: In most clinical studies, recommended doses of 20-40 mg HBB were injected, mainly intravenously. Fast pain reduction was achieved by HBB in renal colic; about 90% of the patients showed good to moderate analgesic responses after 30 min and the onset of action was noticeable within 10 min. Similarly, a pain reduction of 42-78% was observed in patients with biliary colic within 30 min after a single intravenous injection of 20 mg. In contrast, no analgesic efficacy of a single injection of 20 mg was found after surgical or shock-wave procedures in the urogenital area. Administration of HBB prior to, or during, radiological imaging distended the gastrointestinal (GI) tract in double-contrast barium and computed tomographic colonography studies and reduced motion artefacts in magnetic resonance imaging. This improved diagnostic image quality and organ visualisation. Pre-medication led to shorter and easier endoscopy in some, but not all, studies. Because of cervical relaxation, HBB shortened total labour duration with 17-67%. It also relieved pain and reduced GI secretions in terminal cancer patients with inoperable bowel obstruction. With regard to its safety profile, parenteral administration of HBB is associated with mild and self-limiting adverse events, typical for anticholinergic drugs. CONCLUSIONS: These clinical results of rapid action and beneficial efficacy combined with good tolerability support the use of HBB in a range of indications related to acute abdominal spasm, in labour and palliative care and for supporting diagnostic and therapeutic abdominal procedures, where spasm may be a problem.

Synthesis and antispasmodic activity of lidocaine derivatives endowed with reduced local anesthetic action.

The present structure-activity relationship (SAR) study focused on chemical modifications of the structure of the local anesthetic lidocaine, and indicated analogues having reduced anesthetic potency, but with superior potency relative to the prototype in preventing anaphylactic or histamine-evoked ileum contraction. From the SAR analysis, 2-(diethylamino)-N-(trifluoromethyl-phenyl) and 2-(diethylamino)-N-(dimethyl-phenyl) acetamides were selected as the most promising compounds. New insights into the applicability of non-anesthetic lidocaine derivatives as templates in drug discovery for allergic syndromes are provided.

Himbacine analogs as muscarinic receptor antagonists--effects of tether and heterocyclic variations.

A number of analogs of the natural product himbacine were synthesized employing variations at the heterocyclic unit and the tether that links the heterocyclic unit to the tricyclic motif. Several of these analogs had M(2) affinity and M(1)/M(2) selectivity comparable to those of himbacine. The structural and stereochemical requirements of the heterocyclic unit for muscarinic binding are discussed in the light of these data.

Synthesis and antispasmodic activity evaluation of bis-(papaverine) analogues.

A new series of N-substituted bis-(tetrahydropapaverine) ring systems have been synthesised in expectation of better antispasmodic activity in comparison with papaverine. The synthesis of the targeted heterocycles is described along with a discussion of their structure activity relationship. The general synthetic methods of bis-(tetrahydropapaverine) analogues involve tetrahydropapaverine, various piperazines, diisocyanates and diisothiocyanates as starting materials. Pharmacological evaluation involves the in vitro antispasmodic activity on a freshly removed guinea pig ileum using a force displacement transducer amplifier connected to a physiograph. Among the analogues synthesized in the present study, N,N'-bis-[2-carbamoyl-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinyl]piperazine (22), was found to be the most potent muscle relaxant (IC(50): 0.31 microM).

Analgesic and antispasmodic activities of 2-(2-nitro-phenyl)-1H-benzimidazole 5-carboxylic acid: evidence for the importance of the 2-(o-substituted phenyl) group.

Benzimidazole 5-carboxylic acid derivatives were investigated for analgesic activity in this study. Of the benzimidazole compounds tested, 2-(2-nitro-phenyl)-1H-benzimidazole 5-carboxylic acid showed remarkable naloxone sensitive analgesic activity in the tail clamp but not in the tail immersion analgesia tests. This centrally active compound showed antispasmodic activity only on KCl induced contractions of isolated rat ileum and not on acetylcholine induced contractions. Acute toxicity of the compounds were >100 mg/kg i.p. mice. It was concluded that substitution of the 2(o-phenyl) by nitro- but not by chloro- or methoxy groups is important for naloxone sensititive analgesic activity of benzimidazole compounds and it was hypothetized that new imidazole compounds having a 2-(o-substituted phenyl) moiety needs to be investigated.

Synthesis and muscarinic M(2) subtype antagonistic activity of enantiomeric pairs of 3-demethylhimbacine (3-norhimbacine) and its C(4)-epimer.

In the course of our studies of the structure-activity relationships of himbacine 1, a potent antagonist of the M(2) subtype of muscarinic receptor, the four title compounds, 2, ent-2, 3, and ent-3, were synthesized with a highly stereoselective intermolecular Diels-Alder reaction of tetrahydroisobenzofuran 4 with achiral furan-2(5H)-one 5 as a key step, followed by simultaneous optical resolution and epimer separation of the racemic intermediates. Among these compounds, 3-demethylhimbacine (3-norhimbacine) 2, bearing an absolute configuration corresponding to that of 1, was found to show more potent muscarinic M(2) subtype receptor binding activity than natural 1.

Synthesis of N-substituted piperazinyl carbamoyl and acetyl derivatives of tetrahydropapaverine: potent antispasmodic agents.

The synthesis and structure-activity-relationship (SAR) for a series of N-substituted piperazinyl carbamoyl 7-15 and piperazinyl acetyl 18-26 derivatives of tetrahydropapaverine have been carried out. The general synthetic methods of carbamoyl tetrahydropapaverine analogues involve N-substituted piperazines and carbamoyl imidazole tetrahydropapaverine as starting materials. Another route for synthesizing these compounds, involving the formation of carbamoyl imidazole piperazine has also been explored. Acylation of tetrahydropapaverine followed by substitution with various piperazinyl moities afforded the acetyl tetrahydropapaverine derivatives. Variously substituted piperazines have been used to monitor the effect of electron releasing and electron withdrawing substituents upon the antispasmodic activity of the molecules. Effect of varying electron densities on the antispasmodic activity, by altering the position of these groups on the benzene ring has also been monitored. Pharmacological methods involve the in vitro antispasmodic activity studies on a freshly removed guinea pig ileum using a force displacement transducer amplifier connected to a physiograph. Among the analogues synthesized in the present study, a promising compound 7, a potent muscle relaxant as compared to papaverine has been obtained.

Synthesis and spasmolytic action of 2-substituted thienopyrimidin-4-one derivatives.

In the search for novel compounds to treat disorders of smooth muscle function, efforts have focused on some 2-substituted thieno[2,3-d]pyrimidin-4-one derivatives that show interesting spasmolytic action. Our laboratories have developed a new series of quaternary salts of 2-substituted thieno[2,3-d]pyrimidin-4-one and thieno[3,2-d]pyrimidin-4-one isomers with therapeutic potential. Thesesubstances were prepared starting from simple derivatives of thiophene. Their spasmolytic activity was evaluated on transmurally stimulated guinea-pig ileum. The most active compounds (IC50 1.12-2.71 microM) 7f-7h, 12d and 12f had the terminal piperidino nucleus in the thioalkyl chain and lacked two methyl groups in the thiophene ring. Their relaxant activity on the isolated ileum was potentiated (approx. 20-25%) by phosphodiesterase inhibitors. Compounds 7f-h, 12d and 12f were less effective in inhibiting contractions of the guinea-pig ileum induced by acetylcholine (IC50 26.7-41.4 microM) or histamine (IC50 41.5-63.4 microM) and had a moderate binding activity to muscarinic receptors in membrane homogenates from the rat heart (M2 sites; pKi values between 5.55+/-0.08 and 5.14+/-0.12; n = 3) and submaxillary gland (M3 sites; pKi values between 6.15+/-0.07 and 5.76+/-0.08; n = 3). Action involving soluble guanylyl cyclase or any potential binding to guinea-pig ventricular L-type calcium channels was not considered likely. It is concluded that at least two different mechanisms of action contribute to their spasmolytic activity.

New metal complexes of 4-methyl-7-hydroxycoumarin sodium salt and their pharmacological activity.

Complexes of copper (II), zinc (II), nickel (II), cobalt (II) and iron (III) with 4-methyl-7-hydroxycoumarin sodium salt (Mendiaxon, Hymecromone) were synthesized by mixing of equimolar amounts of the respective metal nitrates and 4-methyl-7-hydroxycoumarin sodium salt in water. The complexes were characterized and identified by elemental analysis, conductivities, IR, 1H NMR spectroscopy and mass spectral data. DTA and TGA have been applied to study the compositions of the compounds. Thermal analysis of the complexes indicate the formation of compounds which correspond to the compositions Met(HL)2 x nH2O, where Met = Cu, Zn, Ni, Co; n = 2, 3 or 4 and Fe(HL)3 x 5H2O. The newly synthesized compounds were assayed for acute intraperitoneal and per oral toxicity, influence on blood clotting time and the most active complex was investigated for spasmolytic activity.

Synthesis and potassium channel opening activity of substituted 10H-benzo[4,5]furo[3,2-b]indole-and 5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acids.

Compounds in a structurally novel series of substituted 10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acids and related 5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acids were prepared and shown to possess potent, bladder-selective smooth muscle relaxant properties and thus are potentially useful for the treatment of urge urinary incontinence. Electrophysiological studies using rat detrusor myocytes have demonstrated that prototype compound 7 produces a significant increase in hyperpolarizing current, which is iberiotoxin (IbTx)-reversed, thus consistent with activation of the large-conductance Ca(2+)-activated potassium channel (BK(Ca)).

The practical synthesis of a uterine relaxant, bis(2-[[(2S)-2-([(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)-phenyl]ethyl]amino)-1,2,3,4-tetrahydronaphthalen-7-yl]oxy]-N,N-dimethylacetamide) sulfate (KUR-1246).

The synthetic route for a uterine relaxant, bis(2-[[(2S)-2-([(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)-phenyl]ethyl]amino)-1,2,3,4-tetrahydronaphthalen-7-yl]oxy]-N,N-dimethylacetamide) sulfate (KUR-1246), was established by the coupling of optically active components, the bromohydrin 14 and the amine 24. We now describe the practical synthesis of these two optically active components. Bromohydrin 14 was obtained by the asymmetric borane reduction of the prochiral phenacyl bromide 13 using a catalyst prepared from aluminum triethoxide and a chiral amino alcohol. The other optically active component 24 was prepared from (S)-AMT.