piperidines and Erectile-Dysfunction

In the last decades, the physiological and pharmacological properties of dopamine receptors were controversial principally because of the lack of selective ligand for some receptor subtypes. Since 1997, some specific D4 agonists have been described and have allowed a therapeutic approach. We report here, compounds described as D4 agonist and when available the SAR. The major studies for physiological implications and their potential biological applications are also reported and principally their interest in erectile dysfunction.

Topics: Animals; Dopamine Agonists; Drug Design; Erectile Dysfunction; Humans; Male; Piperazines; Piperidines; Receptors, Dopamine D4; Structure-Activity Relationship

We aimed to explore the effect of tofacitinib on erectile dysfunction (ED), as well as disease activity and health related quality of life in male patients with rheumatoid arthritis (RA). Forty eight male RA patients with ED were included. Demographic and clinical data at baseline and 6 month of treatment were recorded from patients' medical records. Disease activity was evaluated with the disease activity score on 28 joints (DAS28), quality of life with Health Assessment Questionnaire-Disability Index (HAQ-DI) and ED with International Index of Erectile Function-5 (IIEF-5). The patients were aged 45.58 [Formula: see text] 2.14 years with a disease duration of 79.33 [Formula: see text] 25.31 months. According to the IIEF-5, 17 (35.4%) patients had severe ED, 10 (20.8%) patients moderate ED, 10 (20.8%) patients mild to moderate ED and 11 (22.9%) patients mild ED. For the entire patient group, baseline median IIEF-5 score was significantly increased from 9.35 (5.30-19.40) to 9.90 (5.20-24.90), baseline median DAS28 was significantly decreased from 5.65 (4.80-6.70) to 5.00 (2.40-6.40), HAQ-DI from 1.70 (1.10-2.40) to 1.15 (0.40-2.20) at 6th month of treatment (all p value < 0.001). Also, quantitative change in IIEF-5 was significantly correlated with changes in DAS28 (r: - 0.735, p < 0.001) and HAQ-DI (r: - 0.700, p < 0.001). Tofacitinib monotherapy may improve ED severity and as well as disease activity and health related quality of life in male patients with RA complaining of ED.

Topics: Arthritis, Rheumatoid; Erectile Dysfunction; Humans; Male; Piperidines; Pyrimidines; Quality of Life; Treatment Outcome

The goal of this work was to demonstrate that Doppler ultrasound (DUS) after pharmacological stimulation of erection (PSE) can be used to evaluate the presence and intensity of a cavernovenous leak (CVL) suspected in erectile dysfunction (ED) patients. The study was built around 50 DUS-PSE exams of penile arteries and veins, which were carried out 3, 5, 10 and 20minutes after pharmacological stimulation. Measured parameters were end diastolic velocity of the cavernous arteries and mean velocity of the deep penile vein and/or penile superficial veins. A score from 0 to 3 was attributed to each according to the recorded velocities. A final score from 0 to 9 was established by adding the three values: patients quoting 0 and 1 were classified as "no leak" (n=8); from 2 to 9 (n=42) as "leaking". Penile computed tomography (CT-scan) under identical pharmacological stimulation identified the cavernovenous leak to be compared with the DUS-PSE results, which were valid in 47 cases (94%), with 97.6% sensitivity and 77.7% specificity. The kappa correlation coefficient for CT-scan diagnosis of suspected CVL was 0.7875 (P<0.001). In addition, we found that end diastolic velocity in the cavernous artery, considered up until now as the gold standard in cases of suspected CVL was insufficient (negative predictive value=47%). In addition to its well-known diagnostic value regarding ED of arterial origin, DUS-PSE is an excellent screening test for CVL, especially in young patients without vascular risk factors who are resistant to medical treatments. For those with well-established CVL, confirmation by CT-scan to discuss possible surgery should be the next step. Moreover, DUS-PSE is useful in postoperative monitoring.

Topics: Adult; Aged; Atropine; Blood Flow Velocity; Computed Tomography Angiography; Dipyridamole; Drug Combinations; Erectile Dysfunction; Humans; Male; Middle Aged; Papaverine; Penile Erection; Penis; Piperidines; Piribedil; Predictive Value of Tests; Recovery of Function; Regional Blood Flow; Reproducibility of Results; Retrospective Studies; Treatment Outcome; Ultrasonography, Doppler, Pulsed; Yohimbine

The relevance of the melanocortin system to sexual activity is well established, and nonselective peptide agonists of the melanocortin receptors have shown evidence of efficacy in human sexual dysfunction. The role of the MC4 receptor subtype has received particular scrutiny, but the sufficiency of its selective activation in potentiating sexual response has remained uncertain owing to conflicting data from studies in preclinical species. We describe here the discovery of a novel series of small-molecule MC4 receptor agonists derived from library hit 2. The addition of methyl substituents at C3 and C5 of the 4-phenylpiperidin-4-ol ring was found to be markedly potency-enhancing, enabling the combination of low nanomolar potencies with full rule-of-five compliance. In general, the series shows only micromolar activity at other melanocortin receptors. Our preferred compound 40a provided significant systemic exposure in humans on both sublingual and oral administration and was safe and well tolerated up to the maximum tested dose. In a pilot clinical study of male erectile dysfunction, the highest dose of 40a tested (200 mg) provided a similar level of efficacy to sildenafil.

Topics: Administration, Intranasal; Administration, Oral; Administration, Sublingual; Animals; Biological Availability; Clinical Trials, Phase I as Topic; Crystallography, X-Ray; Dogs; Erectile Dysfunction; Hepatocytes; Humans; In Vitro Techniques; Male; Microsomes, Liver; Models, Molecular; Piperidines; Pyrrolidines; Randomized Controlled Trials as Topic; Rats; Receptor, Melanocortin, Type 4; Stereoisomerism; Structure-Activity Relationship

We report the discovery and optimization of substituted 2-piperazinecarboxamides as potent and selective agonists of the melanocortin subtype-4 receptor. Further in vivo development of lead agonist, MB243, is disclosed.

Topics: Animals; Dogs; Erectile Dysfunction; Haplorhini; Male; Mice; Obesity; Piperazines; Piperidines; Rats; Receptor, Melanocortin, Type 4

We have reported that adrenomedullin (AM)-induced vasodilation is at least in part nitric oxide (NO)-cGMP-dependent in the rat. Although it is well known that NO is much involved in the erectile function, it is controversial as to whether AM influences the erectile function. Thus, we examined the effects of AM on intracavernous pressure (ICP) during penile erection. The left carotid artery of rats was cannulated to monitor of mean arterial pressure (MAP). Bipolar electrodes were positioned on the cavernous nerve. The right cavernous body was cannulated with a needle connected to a pressure transducer to monitor ICP. Electrical stimulation (ES) increased ICP in a voltage-dependent manner. Elevation of ICP continued during ES. The intracavernous injection of 0.5 nmol AM significantly potentiated ES-induced increases in both maximal developed ICP/MAP and area under the curve (ICP trace; AUC). Since AM slightly lowered MAP, ICP was normalized by MAP. i.v. administration of N(omega)-nitro-L-arginine, a NO synthase inhibitor, markedly decreased AM/ES-induced ICP elevation. However, in the presence of E-4021, a cGMP-specific phosphodiesterase inhibitor, AM further increased both ICP/MAP and AUC. These results suggest that a NO-cGMP pathway is involved in the regulation of AM-induced rat cavernous vasorelaxation.

Topics: Adrenomedullin; Animals; Arginine; Cyclic GMP; Disease Models, Animal; Enzyme Inhibitors; Erectile Dysfunction; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Penile Erection; Peptides; Phosphodiesterase Inhibitors; Piperidines; Quinazolines; Rats; Rats, Wistar

This was an open preliminary study of 36 unselected men suffering from erectile dysfunction (DE) for the evaluation of the deep dorsal vein of the penis (VDP) by duplex scan (EDP). All men had an intravenous injection (IIC) with a vaso active agent: alprostadil (Edex) (n = 24), a mixture of papaverine ifenprodyl tartrate (Vadilex) (n = 4) or papaverine, ifenprodyl tartrate and alprostadil (n = 7). The deep dorsal vein was evaluated, with a 13 mHz mechanical probe 5 and 10 minutes after the injection, during visual sexual stimulation (SSV) carried on for 10 mn, and 3 mn after having stopped SSV. The influence of deep breathing and contraction of the ischio and bulbo-cavernous muscles was recorded at each of the periods.. The deep dorsal vein was identified in all cases. After pharmacological stimulation flow was present in 61% of the cases, with a statistically significant difference between alprostadil (80%) and both mixtures (20%). The addition of sexual stimulation caused flow to disappear in 64% of the cases (91% for the mixture and 44% for alprostadil). There was a range of variation under breathing and muscular contraction which deserves further evaluation.. 1) The deep dorsal vein is easily studied under duplex scan and should be part of the routine examination of the vascular component of erection during erectile dysfunction. 2) The vein is subjected to modification of flow after intracavernous injection and sexual stimulation which varies with the agent injected and the clinical condition of the patients. 3) Absent flow early after injection seems to be predictive of the possibility of a prolonged erection.

Topics: Adult; Aged; Alprostadil; Erectile Dysfunction; Humans; Male; Middle Aged; Penis; Piperidines; Ultrasonography, Doppler, Pulsed; Vasodilator Agents; Veins

Of 615 patients with impotence of varying etiologies who were followed from 12 to 96 months after the institution of intracavernous self-injection therapy with vasoactive drugs (papaverine alone, papaverine and alpha-blockers, and Ceritine, a new multilevel acting drug) 87% (533 patients) returned for followup visits or were regularly contacted. Of these patients sexual activity was restored in 91%. The dropout rate was 11.25%. The 114 episodes of prolonged erections among 51 patients (4.57%) represented less than 3 per 1,000 of the 34,875 recorded injections. All patients were treated without complications. The percentage of patients suffering from nodules or permanent deformations was 2.8%. There were no cases of intracavernous fibrosis. The percentage of satisfied patients (satisfaction index 7 or greater) was 84.8%. Improvement in spontaneous erections during sexual intercourse was obtained in 65% of the cases: 15% no longer needed self-injections and 50% only used them occasionally while 35% remained entirely dependent.

Topics: Adrenergic alpha-Antagonists; Atropine; Consumer Behavior; Dipyridamole; Drug Combinations; Drug Therapy, Combination; Erectile Dysfunction; Follow-Up Studies; Humans; Male; Middle Aged; Papaverine; Penile Erection; Penis; Piperidines; Piribedil; Regional Blood Flow; Self Administration; Time Factors; Yohimbine

Topics: Adult; Ejaculation; Erectile Dysfunction; Humans; Male; Phenothiazines; Piperidines