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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone and Men's Health Articles
Synthetic Receptor Can Distinguish Between Male and Female Steroid Hormones
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<blockquote data-quote="madman" data-source="post: 146969" data-attributes="member: 13851"><p><span style="font-size: 22px"><strong><span style="color: rgb(0, 0, 0)">Abstract</span></strong></span></p><p><strong>Biological receptors <span style="color: rgb(184, 49, 47)">distinguish and bind steroid sex hormones</span>, e.g., <span style="color: rgb(184, 49, 47)">androgen-, progestogen-, and estrogen-type hormones</span>, with <span style="color: rgb(184, 49, 47)">high selectivity.</span></strong> To date, artificial molecular receptors have been unable to discriminate between these classes of biosubstrates. <strong>Here, we report that an <span style="color: rgb(184, 49, 47)">artificial polyaromatic receptor</span> preferentially binds <span style="color: rgb(184, 49, 47)">a single molecule of androgenic hormones</span>, known as <span style="color: rgb(184, 49, 47)">“male” hormones (indicated with <em>m</em>)</span>, over <span style="color: rgb(184, 49, 47)">progestogens and estrogens</span>, known as <span style="color: rgb(184, 49, 47)">“female” hormones (indicated with <em>f</em>)</span>, in water. Competitive experiments established <span style="color: rgb(0, 0, 0)">the</span><span style="color: rgb(184, 49, 47)"> binding selectivity </span>of the <span style="color: rgb(184, 49, 47)">synthetic receptor</span> for various sex hormones to be <span style="color: rgb(184, 49, 47)">testosterone (<em>m</em>) > androsterone (<em>m</em>) >> progesterone (<em>f</em>) > β-estradiol (<em>f</em>) > pregnenolone (<em>f</em>) > estriol (<em>f</em>).</span></strong> <strong>These bindings are driven by the <span style="color: rgb(184, 49, 47)">hydrophobic effect</span>, and the observed selectivity arises from <span style="color: rgb(184, 49, 47)">multiple CH-π contacts and hydrogen-bonding interactions in the semirigid polyaromatic cavity. </span>Furthermore, <span style="color: rgb(184, 49, 47)">micromolar fluorescence detection of androgen</span> was demonstrated using the <span style="color: rgb(184, 49, 47)">receptor containing a fluorescent dye in water.</span></strong></p><p></p><p></p><p></p><p></p><p></p><p></p><p></p><p></p><p><span style="font-size: 22px"><strong>DISCUSSION</strong></span></p><p><strong>We have realized the <span style="color: rgb(184, 49, 47)">discrimination</span> between <span style="color: rgb(184, 49, 47)">steroid male </span><span style="color: rgb(0, 0, 0)">and </span><span style="color: rgb(184, 49, 47)">female hormones</span> by a <span style="color: rgb(184, 49, 47)">synthetic molecular receptor in water.</span> The <span style="color: rgb(184, 49, 47)">binding affinity</span> resembles that of <span style="color: rgb(184, 49, 47)">natural androgen receptors</span>: <span style="color: rgb(44, 130, 201)">Androgenic male hormones</span> are <span style="color: rgb(44, 130, 201)">predominantly encapsulated </span>by the <span style="color: rgb(44, 130, 201)">receptor </span>even from <span style="color: rgb(44, 130, 201)">mixtures including large excess progestogenic and estrogenic female hormones.</span> The <span style="color: rgb(184, 49, 47)">key </span>of the <span style="color: rgb(184, 49, 47)">present achievement</span> is using a <span style="color: rgb(184, 49, 47)">semirigid nanocavity</span> surrounded by <span style="color: rgb(184, 49, 47)">polyaromatic frameworks</span> linked by <span style="color: rgb(184, 49, 47)">metal ions</span>, which can <span style="color: rgb(184, 49, 47)">deform the shape </span>to enhance <span style="color: rgb(184, 49, 47)">interactions</span> between the <span style="color: rgb(184, 49, 47)">substrates</span> and <span style="color: rgb(184, 49, 47)">cavity.</span> The <span style="color: rgb(184, 49, 47)">combination</span> of the <span style="color: rgb(184, 49, 47)">polyaromatic receptor </span>with <span style="color: rgb(184, 49, 47)">high androgen affinity</span> and <span style="color: rgb(184, 49, 47)">advanced analytical methods </span>based on <span style="color: rgb(184, 49, 47)">single-molecule detection</span> (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474769/#R1" target="_blank"><em>1</em></a>–<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474769/#R3" target="_blank"><em>3</em></a>) would develop <span style="color: rgb(184, 49, 47)">novel ultrasensitive analytical devices</span> for <span style="color: rgb(184, 49, 47)">steroid sex hormones</span>, one of the most <span style="color: rgb(184, 49, 47)">important</span> and <span style="color: rgb(184, 49, 47)">complex biosubstrates </span>with <span style="color: rgb(184, 49, 47)">high physiological activities.</span></strong></p><p></p><p></p><p></p><p></p><p></p><p>[ATTACH=full]7359[/ATTACH]</p><p><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474769/figure/F1/" target="_blank">Fig. 1</a></p><p><strong>Structures of steroid sex hormones, a natural androgen receptor, and a synthetic receptor.</strong></p><p></p><p><span style="color: rgb(184, 49, 47)">(<strong>A</strong>) </span><strong><span style="color: rgb(184, 49, 47)">Tetracyclic framework of steroid sex hormones. </span></strong>(<strong>B</strong>) <span style="color: rgb(0, 0, 0)"><strong>Crystal structures of a human androgen receptor (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474769/#R6" target="_blank"><em>6</em></a>, left) and synthetic receptor 1 (right) shown at the same scale. The binding pocket and cavity are highlighted in yellow.</strong></span> <span style="color: rgb(184, 49, 47)">(<strong>C</strong>) <strong>Polyaromatic receptor 1 used here and space-filling representation of the core framework (based on the crystal structure).</strong></span> (<strong>D</strong>) <strong><span style="color: rgb(0, 0, 0)">Representative male hormone, testosterone (2a), and female hormones, progesterone (3a) and β-estradiol (4a).</span></strong></p><p></p><p></p><p></p><p></p><p>[ATTACH=full]7360[/ATTACH]</p><p><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474769/figure/F2/" target="_blank">Fig. 2</a></p><p><strong>Selective binding of testosterone by receptor 1 from mixtures.</strong></p><p><strong><span style="color: rgb(184, 49, 47)">(A) Schematic representation of the selective binding of testosterone (2a) by receptor 1 from a mixture of 2a, progesterone (3a), and β-estradiol (4a) (1:1:1 or 1:100:100 ratio) in water. </span><span style="color: rgb(0, 0, 0)">1H NMR spectra (500 MHz, D2O) of (B) receptor 1 and</span> </strong><span style="color: rgb(0, 0, 0)"><strong>(C) products obtained from an equimolar mixture of 2a, 3a, and 4a in the presence of 1 at 60°C for 10 min (gray square, 1•3a) and (D) 1•2a.</strong></span> <strong><span style="color: rgb(184, 49, 47)">(E) Changes of the 1H NMR chemical shifts (Δδ in ppm) of 2a upon encapsulation by 1. </span></strong><span style="color: rgb(0, 0, 0)"><strong>(F) ESI-TOF MS spectrum (H2O, room temperature) of 1•2a.</strong></span></p><p></p><p></p><p></p><p></p><p>[ATTACH=full]7361[/ATTACH]</p><p><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474769/figure/F3/" target="_blank">Fig. 3</a></p><p><strong>X-ray crystal structure of 1’•2a.</strong></p><p><strong><span style="color: rgb(0, 0, 0)">(A) Space-filling (for 2a) and cylindrical (for 1’) representation and</span></strong> <strong><span style="color: rgb(184, 49, 47)">(B) space-filling representation (the peripheral substituents of 1’ are replaced by hydrogen atoms for clarity). </span>(C) Highlighted positions of 2a inside the polyaromatic shell of 1’ (three different views).</strong> <span style="color: rgb(184, 49, 47)"><strong>(D) Highlighted host-guest interactions of 1’•2a in the cavity (blue, orange, and red dashed lines are CH-π, OH-π, and hydrogen-bonding interactions, respectively)</strong></span></p><p></p><p></p><p></p><p></p><p>[ATTACH=full]7362[/ATTACH]</p><p><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474769/figure/F4/" target="_blank">Fig. 4</a></p><p><strong>Binding affinity of receptor 1 toward male hormones.</strong></p><p><span style="color: rgb(184, 49, 47)"><strong>(A) Schematic representation of the binding preference of receptor 1 toward male hormones 2a to 2e in water.</strong> </span><strong>(B) 1H NMR spectra (500 MHz, D2O, room temperature) of 1•2a (top), 1•2c (middle), and the product (bottom) obtained from an equimolar mixture of 2a and 2c with 1 (blue circle, 1•2a; pale blue square, 1•2c).</strong> <span style="color: rgb(184, 49, 47)"><strong>(C) 1H NMR spectra (500 MHz, D2O, room temperature) of 1•2a (top), 1•2d (middle), and the product (bottom) obtained from an equimolar mixture of 2a and 2d with 1 (blue circle, 1•2a; pale blue triangle, 1•2d)</strong></span><strong><span style="color: rgb(184, 49, 47)">.</span> Binding preference of 1 toward (D) 2a and methyltestosterone (5a) and (E) 2d and adrenosterone (5b) in water.</strong></p><p></p><p></p><p></p><p></p><p>[ATTACH=full]7363[/ATTACH]</p><p><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474769/figure/F5/" target="_blank">Fig. 5</a></p><p><strong>Binding affinity of receptor 1 toward female hormones.</strong></p><p><strong><span style="color: rgb(184, 49, 47)">(A) Schematic representation of the binding preference of receptor 1 toward female hormones 3a to 3c and 4a to 4c in water.</span></strong><span style="color: rgb(0, 0, 0)"><strong> 1H NMR spectra (500 MHz, D2O, room temperature) of products obtained from equimolar mixtures of (B) 2e and 3a, (C) 3a and 4a, and (D) 4a and 4c with 1.</strong></span> <strong><span style="color: rgb(184, 49, 47)">(E) Binding preference of 1 toward 3b and 5α-androstane (5c) in water.</span></strong></p><p></p><p></p><p></p><p></p><p>[ATTACH=full]7364[/ATTACH]</p><p><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474769/figure/F6/" target="_blank">Fig. 6</a></p><p><strong>Fluorescent detection of testosterone by receptor-dye complex 1•6.</strong></p><p><strong><span style="color: rgb(184, 49, 47)">(A) Schematic representation of nanogram-scale fluorescent detection of male hormone 2a using one drop of an aqueous 1•6 solution (8 μM) and their photographs (λex = 356 nm) on a petri dish. </span>(B) Fluorescence spectra (room temperature, λex = 423 nm) of a H2O solution of 1•6 (78 μM, 0.5 ml) before and after addition of 2a (45 nmol) and their photographs (λex = 356 nm).</strong></p></blockquote><p></p>
[QUOTE="madman, post: 146969, member: 13851"] [SIZE=22px][B][COLOR=rgb(0, 0, 0)]Abstract[/COLOR][/B][/SIZE] [B]Biological receptors [COLOR=rgb(184, 49, 47)]distinguish and bind steroid sex hormones[/COLOR], e.g., [COLOR=rgb(184, 49, 47)]androgen-, progestogen-, and estrogen-type hormones[/COLOR], with [COLOR=rgb(184, 49, 47)]high selectivity.[/COLOR][/B] To date, artificial molecular receptors have been unable to discriminate between these classes of biosubstrates. [B]Here, we report that an [COLOR=rgb(184, 49, 47)]artificial polyaromatic receptor[/COLOR] preferentially binds [COLOR=rgb(184, 49, 47)]a single molecule of androgenic hormones[/COLOR], known as [COLOR=rgb(184, 49, 47)]“male” hormones (indicated with [I]m[/I])[/COLOR], over [COLOR=rgb(184, 49, 47)]progestogens and estrogens[/COLOR], known as [COLOR=rgb(184, 49, 47)]“female” hormones (indicated with [I]f[/I])[/COLOR], in water. Competitive experiments established [COLOR=rgb(0, 0, 0)]the[/COLOR][COLOR=rgb(184, 49, 47)] binding selectivity [/COLOR]of the [COLOR=rgb(184, 49, 47)]synthetic receptor[/COLOR] for various sex hormones to be [COLOR=rgb(184, 49, 47)]testosterone ([I]m[/I]) > androsterone ([I]m[/I]) >> progesterone ([I]f[/I]) > β-estradiol ([I]f[/I]) > pregnenolone ([I]f[/I]) > estriol ([I]f[/I]).[/COLOR][/B] [B]These bindings are driven by the [COLOR=rgb(184, 49, 47)]hydrophobic effect[/COLOR], and the observed selectivity arises from [COLOR=rgb(184, 49, 47)]multiple CH-π contacts and hydrogen-bonding interactions in the semirigid polyaromatic cavity. [/COLOR]Furthermore, [COLOR=rgb(184, 49, 47)]micromolar fluorescence detection of androgen[/COLOR] was demonstrated using the [COLOR=rgb(184, 49, 47)]receptor containing a fluorescent dye in water.[/COLOR][/B] [SIZE=22px][B]DISCUSSION[/B][/SIZE] [B]We have realized the [COLOR=rgb(184, 49, 47)]discrimination[/COLOR] between [COLOR=rgb(184, 49, 47)]steroid male [/COLOR][COLOR=rgb(0, 0, 0)]and [/COLOR][COLOR=rgb(184, 49, 47)]female hormones[/COLOR] by a [COLOR=rgb(184, 49, 47)]synthetic molecular receptor in water.[/COLOR] The [COLOR=rgb(184, 49, 47)]binding affinity[/COLOR] resembles that of [COLOR=rgb(184, 49, 47)]natural androgen receptors[/COLOR]: [COLOR=rgb(44, 130, 201)]Androgenic male hormones[/COLOR] are [COLOR=rgb(44, 130, 201)]predominantly encapsulated [/COLOR]by the [COLOR=rgb(44, 130, 201)]receptor [/COLOR]even from [COLOR=rgb(44, 130, 201)]mixtures including large excess progestogenic and estrogenic female hormones.[/COLOR] The [COLOR=rgb(184, 49, 47)]key [/COLOR]of the [COLOR=rgb(184, 49, 47)]present achievement[/COLOR] is using a [COLOR=rgb(184, 49, 47)]semirigid nanocavity[/COLOR] surrounded by [COLOR=rgb(184, 49, 47)]polyaromatic frameworks[/COLOR] linked by [COLOR=rgb(184, 49, 47)]metal ions[/COLOR], which can [COLOR=rgb(184, 49, 47)]deform the shape [/COLOR]to enhance [COLOR=rgb(184, 49, 47)]interactions[/COLOR] between the [COLOR=rgb(184, 49, 47)]substrates[/COLOR] and [COLOR=rgb(184, 49, 47)]cavity.[/COLOR] The [COLOR=rgb(184, 49, 47)]combination[/COLOR] of the [COLOR=rgb(184, 49, 47)]polyaromatic receptor [/COLOR]with [COLOR=rgb(184, 49, 47)]high androgen affinity[/COLOR] and [COLOR=rgb(184, 49, 47)]advanced analytical methods [/COLOR]based on [COLOR=rgb(184, 49, 47)]single-molecule detection[/COLOR] ([URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474769/#R1'][I]1[/I][/URL]–[URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474769/#R3'][I]3[/I][/URL]) would develop [COLOR=rgb(184, 49, 47)]novel ultrasensitive analytical devices[/COLOR] for [COLOR=rgb(184, 49, 47)]steroid sex hormones[/COLOR], one of the most [COLOR=rgb(184, 49, 47)]important[/COLOR] and [COLOR=rgb(184, 49, 47)]complex biosubstrates [/COLOR]with [COLOR=rgb(184, 49, 47)]high physiological activities.[/COLOR][/B] [ATTACH=full]7359[/ATTACH] [URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474769/figure/F1/']Fig. 1[/URL] [B]Structures of steroid sex hormones, a natural androgen receptor, and a synthetic receptor.[/B] [COLOR=rgb(184, 49, 47)]([B]A[/B]) [/COLOR][B][COLOR=rgb(184, 49, 47)]Tetracyclic framework of steroid sex hormones. [/COLOR][/B]([B]B[/B]) [COLOR=rgb(0, 0, 0)][B]Crystal structures of a human androgen receptor ([URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474769/#R6'][I]6[/I][/URL], left) and synthetic receptor 1 (right) shown at the same scale. The binding pocket and cavity are highlighted in yellow.[/B][/COLOR] [COLOR=rgb(184, 49, 47)]([B]C[/B]) [B]Polyaromatic receptor 1 used here and space-filling representation of the core framework (based on the crystal structure).[/B][/COLOR] ([B]D[/B]) [B][COLOR=rgb(0, 0, 0)]Representative male hormone, testosterone (2a), and female hormones, progesterone (3a) and β-estradiol (4a).[/COLOR][/B] [ATTACH=full]7360[/ATTACH] [URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474769/figure/F2/']Fig. 2[/URL] [B]Selective binding of testosterone by receptor 1 from mixtures. [COLOR=rgb(184, 49, 47)](A) Schematic representation of the selective binding of testosterone (2a) by receptor 1 from a mixture of 2a, progesterone (3a), and β-estradiol (4a) (1:1:1 or 1:100:100 ratio) in water. [/COLOR][COLOR=rgb(0, 0, 0)]1H NMR spectra (500 MHz, D2O) of (B) receptor 1 and[/COLOR] [/B][COLOR=rgb(0, 0, 0)][B](C) products obtained from an equimolar mixture of 2a, 3a, and 4a in the presence of 1 at 60°C for 10 min (gray square, 1•3a) and (D) 1•2a.[/B][/COLOR] [B][COLOR=rgb(184, 49, 47)](E) Changes of the 1H NMR chemical shifts (Δδ in ppm) of 2a upon encapsulation by 1. [/COLOR][/B][COLOR=rgb(0, 0, 0)][B](F) ESI-TOF MS spectrum (H2O, room temperature) of 1•2a.[/B][/COLOR] [ATTACH=full]7361[/ATTACH] [URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474769/figure/F3/']Fig. 3[/URL] [B]X-ray crystal structure of 1’•2a. [COLOR=rgb(0, 0, 0)](A) Space-filling (for 2a) and cylindrical (for 1’) representation and[/COLOR][/B] [B][COLOR=rgb(184, 49, 47)](B) space-filling representation (the peripheral substituents of 1’ are replaced by hydrogen atoms for clarity). [/COLOR](C) Highlighted positions of 2a inside the polyaromatic shell of 1’ (three different views).[/B] [COLOR=rgb(184, 49, 47)][B](D) Highlighted host-guest interactions of 1’•2a in the cavity (blue, orange, and red dashed lines are CH-π, OH-π, and hydrogen-bonding interactions, respectively)[/B][/COLOR] [ATTACH=full]7362[/ATTACH] [URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474769/figure/F4/']Fig. 4[/URL] [B]Binding affinity of receptor 1 toward male hormones.[/B] [COLOR=rgb(184, 49, 47)][B](A) Schematic representation of the binding preference of receptor 1 toward male hormones 2a to 2e in water.[/B] [/COLOR][B](B) 1H NMR spectra (500 MHz, D2O, room temperature) of 1•2a (top), 1•2c (middle), and the product (bottom) obtained from an equimolar mixture of 2a and 2c with 1 (blue circle, 1•2a; pale blue square, 1•2c).[/B] [COLOR=rgb(184, 49, 47)][B](C) 1H NMR spectra (500 MHz, D2O, room temperature) of 1•2a (top), 1•2d (middle), and the product (bottom) obtained from an equimolar mixture of 2a and 2d with 1 (blue circle, 1•2a; pale blue triangle, 1•2d)[/B][/COLOR][B][COLOR=rgb(184, 49, 47)].[/COLOR] Binding preference of 1 toward (D) 2a and methyltestosterone (5a) and (E) 2d and adrenosterone (5b) in water.[/B] [ATTACH=full]7363[/ATTACH] [URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474769/figure/F5/']Fig. 5[/URL] [B]Binding affinity of receptor 1 toward female hormones. [COLOR=rgb(184, 49, 47)](A) Schematic representation of the binding preference of receptor 1 toward female hormones 3a to 3c and 4a to 4c in water.[/COLOR][/B][COLOR=rgb(0, 0, 0)][B] 1H NMR spectra (500 MHz, D2O, room temperature) of products obtained from equimolar mixtures of (B) 2e and 3a, (C) 3a and 4a, and (D) 4a and 4c with 1.[/B][/COLOR] [B][COLOR=rgb(184, 49, 47)](E) Binding preference of 1 toward 3b and 5α-androstane (5c) in water.[/COLOR][/B] [ATTACH=full]7364[/ATTACH] [URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474769/figure/F6/']Fig. 6[/URL] [B]Fluorescent detection of testosterone by receptor-dye complex 1•6. [COLOR=rgb(184, 49, 47)](A) Schematic representation of nanogram-scale fluorescent detection of male hormone 2a using one drop of an aqueous 1•6 solution (8 μM) and their photographs (λex = 356 nm) on a petri dish. [/COLOR](B) Fluorescence spectra (room temperature, λex = 423 nm) of a H2O solution of 1•6 (78 μM, 0.5 ml) before and after addition of 2a (45 nmol) and their photographs (λex = 356 nm).[/B] [/QUOTE]
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Testosterone and Men's Health Articles
Synthetic Receptor Can Distinguish Between Male and Female Steroid Hormones
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