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Biomedical subjects

A Leonardi

Publications and source records attributed to A Leonardi.

At least 37 records · Page 2Linked to original sources
PubMed2000

Tear and serum soluble leukocyte activation markers in conjunctival allergic diseases.

PURPOSE: To measure markers of leukocyte activation in patients with an exclusively ocular inflammatory or bacterial disease. METHODS: Neutrophil myeloperoxidase, eosinophil cationic protein, eosinophil neurotoxin, and soluble interleukin-2 receptor were measured in serum and tears of 17 patients with allergic vernal keratoconjunctivitis, seven with atopic keratoconjunctivitis, 11 with seasonal allergic conjunctivitis, seven with giant papillary conjunctivitis, 13 with rosacea blepharokeratoconjunctivitis, seven with bacterial conjunctivitis, and 13 normal subjects as controls. RESULTS: In serum of patients with vernal and atopic keratoconjunctivitis, levels of eosinophil cationic protein, eosinophil neurotoxin, and interleukin-2 receptor were significantly increased compared with control subjects but were not correlated with the severity of ocular symptoms. In tears of patients with vernal and atopic keratoconjunctivitis and seasonal allergic conjunctivitis, as well as in the nonallergic diseases, rosacea blepharokeratoconjunctivitis and bacterial conjunctivitis, levels of eosinophil cationic protein, neurotoxin, and interleukin-2 receptor were significantly increased compared with control subjects. The highest values of these markers were found in vernal keratoconjunctivitis samples. Neutrophil myeloperoxidase was significantly increased in vernal and atopic keratoconjunctivitis, rosacea blepharokeratoconjunctivitis, and bacterial conjunctivitis. In vernal keratoconjunctivitis, tear markers were correlated to the clinical score of the disease, but not with cytology. CONCLUSIONS: Tear histamine was measured in 10 allergic patients after allergen challenge. Although none of the above markers can be considered specific to a single disease, their measurement may still be useful for the quantification of local cell activation in ocular inflammatory diseases.

Adolescent↗
PubMed2000

Receptors in cardiovascular disease: review and introduction.

Despite recent encouraging declines, cardiovascular disease (CVD) is still responsible for about 50% of premature death in the Western industrialized countries, greater than cancer, AIDS and accidents, combined. Different aspects of the disease have been considered and the main currently available and possible future drugs whose effect is based on interaction with a receptor have been reviewed. Catecholamines receptors ligands, mainly beta-blockers, and the new angiotensin II antagonists represent the most important classes among the established therapies. Investigational approaches such as the oral glycoprotein GPIIb/IIIa antagonists and endothelin, adenosine and neuropeptide Y receptors ligands are discussed. Receptorology represents just a part of the therapeutical approach to CVD, where other classes of drugs with enzyme or ionic channel based mechanisms are largely used and innovative therapies based on the most advanced research techniques could early become reality.

Animals↗
PubMed2000

The alpha 1a and alpha 1b-adrenergic receptor subtypes: molecular mechanisms of receptor activation and of drug action.

In this chapter we summarize some aspects of the structure-functional relationship of the alpha 1a and alpha 1b-adrenergic receptor subtypes related to the receptor activation process as well as the effect of different alpha-blockers on the constitutive activity of the receptor. Molecular modeling of the alpha 1a and alpha 1b-adrenergic receptor subtypes and computational simulation of receptor dynamics were useful to interpret the experimental findings derived from site directed mutagenesis studies.

Animals↗
PubMed2000

Role of histamine in allergic conjunctivitis.

Histamine remains the main mediator released by both specific allergic and non-specific mast cell activation. Histamine is the classic mediator of itching, flare and redness. The effects of histamine in allergic conjunctivitis are mediated by H1-receptor activation on blood vessels and nociceptive nerves. Histamine effects may be prolonged and exaggerated since a defect in the histaminase enzymes has been recently demonstrated in VKC. The effects of histamine on conjunctival tissues may be more complex than those manifested by the simple symptom of itching. In fact, proinflammatory effects of histamine on conjunctival epithelial cells and fibroblasts have been demonstrated. Preliminary results showed that the H1 antagonist, emedastine, reduces significantly cytokine production from histamine-stimulated fibroblasts.

Conjunctivitis, Allergic↗
PubMed2000

Safety and efficacy comparison of emedastine 0.05% ophthalmic solution compared to levocabastine 0.05% ophthalmic suspension in pediatric subjects with allergic conjunctivitis. Emadine Study Group.

PURPOSE: To determine the efficacy and tolerance of emedastine 0.05% ophthalmic solution compared to levocabastine 0.05% ophthalmic suspension in pediatric subjects. METHODS AND MATERIALS: In a randomized, double-masked, parallel controlled study, emedastine 0.05% ophthalmic solution BID was compared to levocabastine 0.05% ophthalmic suspension BID, for control of the signs and symptoms of allergic conjunctivitis in pediatric subjects ages 3-16. Subjects who met all inclusion and exclusion criteria received masked study medication with instructions to instill drops twice daily, in the morning and evening. A diary was completed by the parents four times daily for the first two and last two weeks of the study. Treatment lasted 42 days. Drug efficacy was assessed at the initial administration in the office at Day 0 and after 3, 7, 14, 30 and 42 days. RESULTS: Overall results showed both drugs have an effect and that emedastine was significantly superior (p < 0.05) to levocabastine for the relief of chemosis on Days 14, 30 and 42; of itching on follow-up Days 30 and 42 (p < 0.05); of redness on Days 30 and 42; for eyelid swelling on Days 14 and 30; and for physician's impression score on Days 7, 14, 30 and 42. CONCLUSION: These results confirm previous preclinical and clinical data on the potent and long acting efficacy of this promising new ophthalmic anti-allergic drug, emedastine in pediatric subjects.

Adolescent↗
PubMed2000

An efficacy and tolerance comparison of emedastine difumarate 0.05% and levocabastine hydrochloride 0.05%: reducing chemosis and eyelid swelling in subjects with seasonal allergic conjunctivitis. Emadine Study Group.

PURPOSE: To compare emedastine ophthalmic solution 0.05% BID to levocabastine ophthalmic suspension 0.05% BID in reducing chemosis, eyelid swelling and other signs and symptoms in subjects with seasonal allergic conjunctivitis. METHODS: In a randomized, double-masked, parallel controlled study, emedastine ophthalmic solution 0.05% BID was compared to levocabastine ophthalmic suspension 0.05% BID for control of chemosis, eyelid swelling and other parameters in the environmental allergy study model. RESULTS: At Days 7, 14, 30 and 42, emedastine was significantly better than levocabastine at controlling chemosis and eyelid swelling (p < 0.05). A statistical trend was seen at Day 3 (0.05 < p < 0.10). Results were clinically relevant at Days 30 and 42. Emedastine was also significantly better at reducing redness and itching at Days 7, 14, 30 and 42 (p < 0.05). CONCLUSION: Emedastine is more efficacious than levocabastine in reducing chemosis, eyelid swelling and other efficacy variables associated with seasonal allergic conjunctivitis.

Adolescent↗
PubMed2000

Anti-inflammatory and antiallergic effects of ketorolac tromethamine in the conjunctival provocation model.

AIM: To study the effect of the topical anti-inflammatory drug, ketorolac, on (1) the clinical allergic reaction induced by the conjunctival provocation test (CPT); (2) the release of tryptase in tears; and (3) the expression of adhesion molecules on the conjunctival epithelium. METHODS: 10 allergic but non-active patients were challenged in both eyes with increasing doses of specific allergen to obtain a positive bilateral reaction and rechallenged, after 1 week, to confirm the allergic threshold dose response. After 2 weeks, a third CPT was then performed bilaterally 30 minutes after topical application of ketorolac in one eye and placebo in the contralateral eye in a double blind fashion. Clinical symptoms and signs were registered 5, 10, 15, and 20 minutes after challenge. The following objective tests were performed: tear tryptase measurement; tear cytology; and conjunctival impression cytology for immunohistochemical expression of ICAM-1 on epithelial cells. RESULTS: Compared with placebo, ketorolac significantly reduced the total clinical score and the itching score in the 20 minutes after challenge (p<0.0005). Tear levels of tryptase were significantly reduced in the ketorolac pretreated eyes compared with placebo (p<0.03). Eosinophils, neutrophils, and lymphocytes in tear cytology were significantly lower in ketorolac treated eyes compared with placebo. A significant difference in the epithelial expression of ICAM-1 was observed between placebo and ketorolac treated eyes (p<0.05). CONCLUSION: Ketorolac proved to be effective in reducing mast cell degranulation, as indicated by significantly decreased tryptase tear levels, as well as the clinical and cytological allergic reaction.

Administration, Topical↗
PubMed2000

Effect of calcium antagonists on glomerular arterioles in spontaneously hypertensive rats.

Through the use of microanatomic techniques, we investigated the effects of treatment with some dihydropyridine-type calcium antagonists (CAs) (ie, lercanidipine, manidipine, and nicardipine) and with the nondihydropyridine-type vasodilator hydralazine on hypertension-dependent glomerular injury and on the morphology of afferent and efferent arterioles in spontaneously hypertensive rats (SHR). Fourteen-week-old male SHR and age-matched normotensive Wistar-Kyoto rats were left untreated (control groups). Four additional groups of 14-week-old SHR were treated for 12 weeks with daily oral doses of 2.5 mg/kg lercanidipine, 5 mg/kg manidipine, 3 mg/kg nicardipine, or 10 mg/kg hydralazine. These treatments decreased systolic blood pressure values to a similar extent in SHR. Signs of glomerular injury, as characterized by glomerulosclerosis, hypertrophy, and an increased number of mesangial cells, were observed in control SHR. The treatment with CAs improved glomerular morphology and decreased the number of mesangial cells. Lercanidipine and manidipine were more effective than nicardipine in countering glomerular injury. In the SHR, both afferent and efferent arterioles revealed luminal narrowing, accompanied by increased wall thickness in efferent arterioles. The dihydropyridine-type derivatives that were tested decreased the luminal narrowing of afferent arterioles. Lercanidipine and manidipine countered the luminal narrowing of efferent arterioles. Hydralazine had no effect on hypertension-dependent glomerular injury or vascular changes. The present data indicate that lercanidipine and manidipine vasodilate afferent and efferent arterioles in SHR. A vasodilatory activity on efferent arteriole, which is not induced by the majority of CAs, may represent an useful property in the treatment of hypertension complicated by renal disease.

Albuminuria↗
PubMed2000

Effects of intracavernous administration of selective antagonists of alpha(1)-adrenoceptor subtypes on erection in anesthetized rats and dogs.

The proerectile properties of three novel alpha(1)-adrenoceptor (alpha(1)-ADR) antagonists with different profiles of selectivity for the alpha(1)-ADR subtypes have been evaluated in anesthetized rats and dogs on intracavernous (IC) injection, in comparison with prazosin and phentolamine. In rats, the tested compounds decreased blood pressure (BP) and increased IC pressure (ICP), as well as the ratio ICP/BP. Rec 15/2841 (alpha(1a)- plus alpha(1L)-ADR-selective antagonist) and Rec 15/2615 (alpha(1b)-ADR selective) were the most potent compounds. The ICP/BP ratios calculated after injection of Rec 15/3039 (alpha(1d)-ADR selective) were not markedly different from those observed after vehicle injection. Prazosin and phentolamine proved poorly active, their main effect being hypotension. Approximate ED(25) values (dose of compound in micrograms inducing 25% increase of ICP/BP ratio) were Rec 15/2615 (22 microgram/kg)>= Rec 15/2841 (29 microgram/kg) > prazosin (136 microgram/kg) > phentolamine (1298 microgram/kg) > Rec 15/3039 (9600 microgram/kg). Submaximal stimulation of the cavernous nerve elicited an ICP rise whose amplitude was not altered by Rec compounds. In contrast, prazosin and phentolamine decreased this ICP rise. All compounds but 15/3039 induced significant increase of the ICP/BP ratio in dogs. Rec 15/2615 proved to be the most interesting compound, inducing significant increases of ICP/BP at doses practically devoid of effects on BP. The rank order of potency in dog in increasing the ICP/BP ratio was similar to that observed in rats. Only at the highest doses tested, all compounds, except Rec 15/3039, decreased the ICP rise elicited by submaximal stimulation of the cavernous nerve. Our data demonstrate that the alpha(1b)- and alpha(1L)-ADR subtypes are functionally relevant for the erectile function in these models, and that alpha(1b)- and/or alpha(1L)-ADR subtypes selective antagonists could represent a real advantage in erectile dysfunction therapy.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2000

Growth factors and collagen distribution in vernal keratoconjunctivitis.

PURPOSE: To study the extracellular composition of giant papillae in vernal keratoconjunctivitis (VKC) and the expression of growth factors that may stimulate fibrosis. METHODS: Upper conjunctival specimens were obtained by biopsy in 9 patients affected by active tarsal VKC (14 eyes) and 10 normal control subjects. Immunohistochemistry was performed on tissue sections using monoclonal antibodies (mAbs) for collagens I, III, and VII; tumor necrosis factor (TNF)-alpha; transforming growth factor (TGF)-ss1; basic fibroblast growth factor (bFGF); and platelet-derived growth factor (PDGF). The mAbs anti-tryptase, anti-CD4, anti-CD68, and anti-EG2 were used as markers for mast cells, T-helper lymphocytes, macrophages, and eosinophils, respectively. Immunofluorescent double-staining for growth factors and cell markers was performed in VKC tissues. RESULTS: Immunostaining was highly positive for collagens I, III, and VII in the subepithelium of VKC conjunctiva. Image analysis showed a significant increase of staining per tissue area for both collagens I and VII and increased basal membrane length. The number of cells positive for TNF-alpha, TGF-ss, bFGF, or PDGF was significantly higher in VKC tissue than in control samples. Double staining showed that eosinophils and macrophages were the main sources of PDGF and that FGF was expressed by 46% of mast cells. Significant PDGF and FGF staining was observed in the conjunctival epithelium and vascular endothelium of all VKC tissues. CONCLUSIONS: In giant papillae of VKC, the extracellular matrix is characterized by overproduction of collagens. Expression of growth factors in the conjunctiva by resident cells (mast cells, epithelial cells, endothelial cells) and inflammatory cells (macrophages, eosinophils) may contribute to papillae formation and fibrosis evolution in chronic ocular allergic diseases.

Adolescent↗
PubMed1999

WB 4101-related compounds. 2. Role of the ethylene chain separating amine and phenoxy units on the affinity for alpha(1)-adrenoreceptor subtypes and 5-HT(1A) receptors.

WB 4101 (1)-related benzodioxanes were synthesized by replacing the ethylene chain separating the amine and the phenoxy units of 1 with a cyclopentanol moiety, a feature of 6, 7-dihydro-5-[[(cis-2-hydroxy-trans-3-phenoxycyclopentyl)amino]meth yl] -2-methylbenzo[b]thiophen-4(5H)-one that was reported to display an intriguing selectivity profile at alpha(1)-adrenoreceptors. This synthesis strategy led to 4 out of 16 possible stereoisomers, which were isolated in the case of (-)-3, (+)-3, (-)-4, and (+)-4 and whose absolute configuration was assigned using a chiral building block for the synthesis of (-)-3 starting from (+)-(2R)-2, 3-dihydro-1,4-benzodioxine-2-carboxylic acid ((+)-9) and (1S,2S, 5S)-2-amino-5-phenoxycyclopentan-1-ol ((+)-10). The aim of this project was to further investigate whether it is possible to differentiate between these compounds with respect to their affinity for alpha(1)-adrenoreceptor subtypes and the affinity for 5-HT(1A) receptors, as 1 binds with high affinity at both receptor systems. The biological profiles of reported compounds at alpha(1)-adrenoreceptor subtypes were assessed by functional experiments in isolated rat vas deferens (alpha(1A)), spleen (alpha(1B)), and aorta (alpha(1D)) and by binding assays in CHO and HeLa cells membranes expressing the human cloned alpha(1)-adrenoreceptor subtypes and 5-HT(1A) receptors, respectively. Furthermore, the functional activity of (-)-3, (+)-3, (-)-4, and (+)-4 toward 5-HT(1A) receptors was evaluated by determining the induced stimulation of [(35)S]GTPgammaS binding in cell membranes from HeLa cells transfected with human cloned 5-HT(1A) receptors. The configuration of the cyclopentane unit determined the affinity profile: a 1R configuration, as in (+)-3 and (-)-4, conferred higher affinity at alpha(1)-adrenoreceptors, whereas a 1S configuration, as in (-)-3 and (+)-4, produced higher affinity for 5-HT(1A) receptors. For the enantiomers (+)-4 and (-)-4 also a remarkable selectivity was achieved. Functionally, the stereoisomers displayed a similar alpha(1)-selectivity profile, that is alpha(1D) > alpha(1B) > alpha(1A), which is different from that exhibited by the reference compound 1. The epimers (-)-3 and (+)-4 proved to be agonists at the 5-HT(1A) receptors, with a potency comparable to that of 5-hydroxytryptamine.

Adrenergic alpha-Agonists↗
PubMed1999

TNF-mediated activation of the stress-activated protein kinase pathway: TNF receptor-associated factor 2 recruits and activates germinal center kinase related.

TNF-induced activation of stress activated protein kinases (SAPKs, Jun NH2-terminal kinases) requires TNF receptor associated factor 2 (TRAF2). TRAF2 is a potent activator of a 95-kDa serine/threonine kinase termed germinal center kinase related (GCKR, also referred to as KHS1), which signals activation of the SAPK pathway. Consistent with a role for GCKR in TNF- induced SAPK activation, a kinase-inactive mutant of GCKR is a dominant negative inhibitor of TRAF2-induced SAPK activation. Here we show that TRAF2 interacts with GCKR. This interaction depended upon the TRAF domain of TRAF2 and the C-terminal 150 aa of GCKR. The full activation of GCKR by TRAF2 required the TRAF2 RING finger domain. TNF treatment of a T cell line, Jurkat, increased both GCRK and SAPK activity and enhanced the coimmunoprecipitation of GCKR with TRAF2. Similar results were found with the B cell line HS-Sultan. These findings are consistent with a model whereby TNF signaling results in the recruitment and activation of GCKR by TRAF2, which leads to SAPK activation.

Amino Acid Sequence↗
PubMed1999

Partial primary structure of a fibrinogenase from the venom of the snake Lachesis stenophrys.

The partial primary structure of an Mr 24,000 non-haemorrhagic metalloproteinase isolated from the venom of the snake Lachesis stenophrys has been determined. The native proteinase was resistant to Edman degradation exhibiting the N-terminal blockade. The pyridylethylated or native proteinase was chemically and enzymatically fragmented and the obtained peptides were separated by gel or reversed-phase chromatography, and sequenced. The metalloproteinase from Lachesis stenophrys contains a putative zinc-chelating sequence HELGHNLGMKH, characteristic for the reprolysin family of zinc-metalloproteinases. It contains six cysteine residues in the standard positions for this group of proteins suggesting the same disulfide bonding. Interestingly, it has almost identical sequence as the metalloproteinase from Lachesis muta muta, LHF-II, which is, however, haemorrhagic. The main structural differences between the two molecules were found in their N-terminal parts and in glycosylation. As the substrate-binding regions of both proteinases are practically identical, we suggest that the absence of haemorrhagicity in Lachesis stenophrys enzyme is due to its lower affinity for the matrix proteins and not due to different substrate specificity.

Amino Acid Sequence↗
PubMed1999

Structure-activity relationships in 1,4-benzodioxan-related compounds. 6. Role of the dioxane unit on selectivity for alpha(1)-adrenoreceptor subtypes.

WB 4101-related benzodioxans 3-9 were synthesized, and their biological profiles at alpha(1)-adrenoreceptor subtypes and 5-HT(1A) serotoninergic receptors were assessed by binding assays in CHO and HeLa cells membranes expressing the human cloned receptors. Furthermore, receptor selectivity of selected benzodioxan derivatives was further determined in functional experiments in isolated rat vas deferens (alpha(1A)) and aorta (alpha(1D)) and guinea pig spleen (alpha(1B)), in additional receptor binding assays in rat cortex membranes containing alpha(2)-adrenoreceptors and 5-HT(2) serotoninergic receptors, and in rat striatum membranes containing D(2) dopaminergic receptors. An analysis of the results of receptor binding experiments for benzodioxan-modified derivatives 3-9 showed high affinity and selectivity toward the alpha(1a)-adrenoreceptor subtype for compounds 3-5 and 7 and a reversed selectivity profile for 9, which was a selective alpha(1d) antagonist. Furthermore, the majority of structural modifications performed on the prototype 1 (WB 4101) led to a marked decrease in the affinity for 5-HT(1A) serotoninergic receptors, which may have relevance in the design of selective alpha(1A)-adrenoreceptor antagonists. The exception to these findings was the chromene derivative 8, which exhibited a 5-HT(1A) partial agonist profile.

Adrenergic alpha-Agonists↗
PubMed1999

Effects of alpha1-adrenoceptor antagonists on agonist and tilt-induced changes in blood pressure: relationships to uroselectivity.

We evaluated the uroselectivity of a series of alpha1-adrenoceptor antagonists by comparing their potency against phenylephrine-induced increases in urethral perfusion pressure and diastolic blood pressure in the anesthetized rabbit and pithed rat. In the rabbit, Rec 15/2739 (N-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-methyl-4-oxo-2-phenyl -4H-1-benzopyran-8-carboxamide) as well as analogs with a chlorine substituent on the methoxyphenyl ring (Rec 15/2869) or this substituent combined with the replacement of the phenyl substituent on the pyran ring by cyclohexyl (Rec 15/3011) were 2-6-fold more potent against the urethral vs. vascular response to phenylephrine. Rec 15/2841 (N-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-methyl-4-oxo-2-cyc lohexy-4H-1-benzopyran-8-carboxamide) was only 1.5-fold more potent against the urethral response. SL 89.0591 and tamsulosin also showed selectivity for the urethral response (2-2.5-fold), while the quinazolines produced equipotent blockade of urethral and vascular responses (selectivity ratio = 0.9-1.1). The urethral selectivities of Rec 15/2739 and its derivatives were confirmed by evaluation of the response to tilt in sedated, hypovolemic rabbits. Phenylephrine challenge assays did not show any of the antagonists, with the exception of terazosin at 300 microg kg(-1), to be uroselective in the rat (selectivity ratios = 0.2-1.5); potentiation of tilt-induced hypotension in the anesthetized rat showed substantial differences from the rabbit, with Rec 15/2739, but not Rec 15/3011 and Rec 15/2841 showing orthostatic effects equivalent to that observed for prazosin. Hence, Rec 15/2739 was uroselective in the rabbit, but not in the rat, while two of its close structural analogs were highly uroselective in both species. An assay for orthostatic activity in the conscious rat yielded different results, showing prazosin and terazosin, but not Rec 15/2739, to cause a reversal of the pressor response to tilt. Hence, the apparent uroselectivity of an alpha1-adrenoceptor antagonist is both species- and assay-dependent.

Adrenergic Agonists↗
PubMed1999

Synthesis, pharmacological evaluation, and structure-activity relationship and quantitative structure-activity relationship studies on novel derivatives of 2,4-diamino-6,7-dimethoxyquinazoline alpha1-adrenoceptor antagonists.

A new series of novel piperazine and non-piperazine derivatives of 2, 4-diamino-6,7-dimethoxyquinazoline was synthesized and evaluated for binding affinity toward alpha1-adrenergic and other G-protein-coupled aminergic receptors. The alpha1-adrenoceptor (AR) subtype selectivity was also investigated for the most interesting compounds. Only compound 16 showed moderate selectivity toward the alpha1b-AR subtype. Selected compounds were tested in vivo in a dog model indicating activity on blood pressure and on the lower urinary tract. Compound 10 showed in vivo potency close to that of prazosin. Powerful interpretative and predictive theoretical QSAR models have been obtained. The theoretical descriptors employed in the rationalization of the alpha1-adrenergic binding affinity depict the key features for receptor binding which can be summarized in an electrostatic interaction between the protonated amine function and a primary nucleophilic site of the receptor, complemented by short-range attractive (polar and dispersive) and repulsive (steric) intermolecular interactions. Moreover, on predictive grounds, the ad hoc derived size and shape QSAR model developed in a previous paper (Rastelli, G.; et al. J. Mol. Struct. 1991, 251, 307-318) proved to be successful in predicting nanomolar alpha1-adrenergic binding affinity for compound 28.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1999

Novel adrenoceptor antagonists with a tricyclic pyrrolodipyridazine skeleton.

A still unknown tricyclic heterocyclic system (5) was synthesized from 6-hydroxy-2-methylpyridazin-3-one and its structure identified as 2,8-dichloro-6-methylpyrrolo[1,2-b:3,4-d']dipyridazin-5(6H)- one by spectroscopic investigations. Selective condensation of 5 with 2-[4-(2-substituted-phenyl)piperazin-1-yl]ethylamine gave the 2-arylpiperazinylethylamino-8-chloro derivatives 6a-c, which were investigated in binding studies toward the three alpha1-adrenergic and 5-HT1A-serotonergic receptor subtypes. They displayed high potency on all the assays and some selectivity for alpha1a and alpha1d subtypes.

Adrenergic Antagonists↗