This work was supported by the Foundation for Science and Technology (FCT), Portugal (projects PTDC/QUI-QUI/113687/2009 and PEst-C/QUI/UI0081/2013). A.G. (SFRH/BD/43531/2008) and M.J.M. (SFRH/BD/61262/2009) thank FCT for grants.

/pdf/chromone-a-valid-scaffold-in-medicinal-chemistry-4qd4v5m5z2.pdf

Chromone: A Valid Scaffold in Medicinal Chemistry

An elongate medical device including an inner elongate member, a reinforcing member, and an outer tubular member is described. The reinforcing member may be a helically wound continuous wire including a first portion having a first cross-sectional profile, a second portion having a second cross-sectional profile, and a transition region located between the first portion and the second portion. The first cross-sectional profile may be different from the second cross-sectional profile. In some embodiments, the first cross-sectional profile may be circular or non-circular and the second cross-sectional profile may be circular or non-circular.

Elongate medical device with continuous reinforcement member

The lower urinary tract constitutes a functional unit controlled by a complex interplay between the central and peripheral nervous systems and local regulatory factors. In the adult, micturition is controlled by a spinobulbospinal reflex, which is under suprapontine control. Several central nervous system transmitters can modulate voiding, as well as, potentially, drugs affecting voiding; for example, noradrenaline, GABA, or dopamine receptors and mechanisms may be therapeutically useful. Peripherally, lower urinary tract function is dependent on the concerted action of the smooth and striated muscles of the urinary bladder, urethra, and periurethral region. Various neurotransmitters, including acetylcholine, noradrenaline, adenosine triphosphate, nitric oxide, and neuropeptides, have been implicated in this neural regulation. Muscarinic receptors mediate normal bladder contraction as well as at least the main part of contraction in the overactive bladder. Disorders of micturition can roughly be classified as disturbances of storage or disturbances of emptying. Failure to store urine may lead to various forms of incontinence, the main forms of which are urge and stress incontinence. The etiology and pathophysiology of these disorders remain incompletely known, which is reflected in the fact that current drug treatment includes a relatively small number of more or less well-documented alternatives. Antimuscarinics are the main-stay of pharmacological treatment of the overactive bladder syndrome, which is characterized by urgency, frequency, and urge incontinence. Accepted drug treatments of stress incontinence are currently scarce, but new alternatives are emerging. New targets for control of micturition are being defined, but further research is needed to advance the pharmacological treatment of micturition disorders.

Pharmacology of the Lower Urinary Tract: Basis for Current and Future Treatments of Urinary Incontinence

This article summarizes anatomical, neurophysiological, pharmacological, and brain imaging studies in humans and animals that have provided insights into the neural circuitry and neurotransmitter mechanisms controlling the lower urinary tract. The functions of the lower urinary tract to store and periodically eliminate urine are regulated by a complex neural control system in the brain, spinal cord, and peripheral autonomic ganglia that coordinates the activity of smooth and striated muscles of the bladder and urethral outlet. The neural control of micturition is organized as a hierarchical system in which spinal storage mechanisms are in turn regulated by circuitry in the rostral brain stem that initiates reflex voiding. Input from the forebrain triggers voluntary voiding by modulating the brain stem circuitry. Many neural circuits controlling the lower urinary tract exhibit switch-like patterns of activity that turn on and off in an all-or-none manner. The major component of the micturition switching circuit is a spinobulbospinal parasympathetic reflex pathway that has essential connections in the periaqueductal gray and pontine micturition center. A computer model of this circuit that mimics the switching functions of the bladder and urethra at the onset of micturition is described. Micturition occurs involuntarily in infants and young children until the age of 3 to 5 years, after which it is regulated voluntarily. Diseases or injuries of the nervous system in adults can cause the re-emergence of involuntary micturition, leading to urinary incontinence. Neuroplasticity underlying these developmental and pathological changes in voiding function is discussed.

/pdf/neural-control-of-the-lower-urinary-tract-2ombjmcwkx.pdf

Neural Control of the Lower Urinary Tract

Storage and periodic expulsion of urine is regulated by a neural control system in the brain and spinal cord that coordinates the reciprocal activity of two functional units in the lower urinary tract (LUT): (a) a reservoir (the urinary bladder) and (b) an outlet (bladder neck, urethra and striated muscles of the urethral sphincter). Control of the bladder and urethral outlet is dependent on three sets of peripheral nerves: parasympathetic, sympathetic and somatic nerves that contain afferent as well as efferent pathways. Afferent neurons innervating the bladder have A-δ or C-fibre axons. Urine storage reflexes are organized in the spinal cord, whereas voiding reflexes are mediated by a spinobulbospinal pathway passing through a coordination centre (the pontine micturition centre) located in the brainstem. Storage and voiding reflexes are activated by mechanosensitive A-δ afferents that respond to bladder distension. Many neurotransmitters including acetylcholine, norepinephrine, dopamine, serotonin, excitatory and inhibitory amino acids, adenosine triphosphate, nitric oxide and neuropeptides are involved in the neural control of the LUT. Injuries or diseases of the nervous system as well as disorders of the peripheral organs can produce LUT dysfunctions including: (1) urinary frequency, urgency and incontinence or (2) inefficient voiding and urinary retention. Neurogenic detrusor overactivity is triggered by C-fibre bladder afferent axons, many of which terminate in the close proximity to the urothelium. The urothelial cells exhibit ‘neuron-like' properties that allow them to respond to mechanical and chemical stimuli and to release transmitters that can modulate the activity of afferent nerves.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1038/sj.bjp.0706604

Integrative control of the lower urinary tract: preclinical perspective

Several novel N-arylpiperazine derivatives were synthesized and tested for their 1) affinity and functional activity on 5-hydroxytryptamine(1A) (5-HT(1A)) receptors in vitro; 2) activity in models predictive of antagonism at somatodendritic and postsynaptic 5-HT(1A) receptors; and 3) effects on the micturition reflex in anesthetized and conscious rats. These studies also included 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine hydrobromide (NAN 190), 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4, 5]decane-7,9-dione dihydrochloride (BMY 7378), and N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl-N-(2-pyridinyl)cyclohex anecarboxamide (WAY 100635). Almost all compounds were found to be potent and selective for the human recombinant 5-HT(1A) receptor, with K(i) values in the nanomolar range. [(35)S]GTPgammaS binding in HeLa cells expressing the recombinant human 5-HT(1A) receptor allowed classification of the compounds into neutral antagonists and partial agonists. Almost all neutral antagonists were active in blocking 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT)-induced forepaw treading in rats (postsynaptic model) and hypothermia in mice (somatodendritic model) with the same potency, whereas compounds showing partial agonistic activity were active in the postsynaptic model but were inactive, or poorly active, in the somatodendritic model. Neutral antagonists potently inhibited volume-induced bladder-voiding contractions in anesthetized rats. Contractions were completely blocked, and the disappearance of bladder contractions lasted 7 to 13 min after the highest doses tested. Furthermore, neutral antagonists increased bladder volume capacity in conscious rats during continuous transvesical cystometry, whereas micturition pressure was only slightly, and not dose-dependently, reduced. Partial agonists were inactive or poorly active, inducing a disappearance time of bladder contractions that did not exceed 6 min in anesthetized rats, and failing to increase bladder volume capacity in conscious rats. These findings indicate that only neutral 5-HT(1A) receptor antagonists are endowed with inhibitory effects on the bladder.

Effect of several 5-hydroxytryptamine(1A) receptor ligands on the micturition reflex in rats: comparison with WAY 100635.

In the present study, more than 75 compounds structurally related to BMY 7378 have been designed and synthesized. Structural variations of each part of the reference molecule have been introduced, obtaining highly selective ligands for the α1d adrenergic receptor. The molecular determinants for selectivity at this receptor are essentially held by the phenyl substituent in the phenylpiperazine moiety. The integration of an extensive SAR analysis with docking simulations using the rhodopsin-based models of the three α1-AR subtypes and of the 5-HT1A receptor provides significant insights into the characterization of the receptor binding sites as well as into the molecular determinants of ligand selectivity at the α1d-AR and the 5-HT1A receptors. The results of multiple copies simultaneous search (MCSS) on the substituted phenylpiperazines together with those of manual docking of compounds BMY 7378 and 69 into the putative binding sites of the α1a-AR, α1b-AR, α1d-AR, and the 5-HT1A receptors suggest that the ...

Synthesis, screening, and molecular modeling of new potent and selective antagonists at the alpha 1d adrenergic receptor.

New DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene) Assisted One-Pot Synthesis of 2,8-Disubstituted 4H-1-Benzopyran-4-ones

N,N-Disubstituted diazocycloalkanes of the formula I (R1=halogen, R2=(C3-C8)-cycloalkyl, R3=(C1-C4)-alkoxy or (C1-C4)-haloalkoxy group, m is 1 or 2 and n is 1 or 2, have affinity for serotonergic receptors. These compounds and their enantiomers, diastereoisomers, N-oxides, polymorphs, solvates and pharmaceutically acceptable salts are useful in the treatment of patients with neuromuscular dysfunction of the lower urinary tract and diseases related to 5-HT1A receptor.

N,N-disubstituted diazocycloalkanes

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 α1-adrenergic and other G-protein-coupled aminergic receptors. The α1-adrenoceptor (AR) subtype selectivity was also investigated for the most interesting compounds. Only compound 16 showed moderate selectivity toward the α1b-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 α1-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...

Synthesis, Pharmacological Evaluation, and Structure−Activity Relationship and Quantitative Structure−Activity Relationship Studies on Novel Derivatives of 2,4-Diamino-6,7-dimethoxyquinazoline α1-Adrenoceptor Antagonists

Gianni Motta

Papers

Effect of several 5-hydroxytryptamine(1A) receptor ligands on the micturition reflex in rats: comparison with WAY 100635.

Synthesis, screening, and molecular modeling of new potent and selective antagonists at the alpha 1d adrenergic receptor.

New DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene) Assisted One-Pot Synthesis of 2,8-Disubstituted 4H-1-Benzopyran-4-ones

N,N-disubstituted diazocycloalkanes

Synthesis, Pharmacological Evaluation, and Structure−Activity Relationship and Quantitative Structure−Activity Relationship Studies on Novel Derivatives of 2,4-Diamino-6,7-dimethoxyquinazoline α1-Adrenoceptor Antagonists